KR102595238B1 - Novel malaria vaccine and antibody that binds to malaria parasite spores. - Google Patents

Abstract

The present invention provides a fragment of the malaria parasite circosporozoite protein according to SEQ ID NO: 1, for example for use in a malaria vaccine. The present invention also provides a nucleic acid encoding a fragment of the malaria parasite circosporozoite protein according to SEQ ID NO: 1, a composition comprising a fragment of the malaria parasite circosporozoite protein according to SEQ ID NO: 1 and a It contains antibodies that bind to fragments of the malaria parasite circosporozoite protein. The antibody according to the present invention binds specifically to P. falciparum sporozoites and can be used for the treatment and/or prevention of malaria.

Description

Novel malaria vaccine and antibody that binds to malaria parasite spores.

The present invention relates to the field of malaria medicine, in particular malaria vaccination and antibodies that bind to plasmodium sporozoites, in particular to plasmodium circumsporozoite protein.

Malaria is a mosquito-borne infectious disease affecting humans and other animals caused by parasitic protozoans of the genus Plasmodium . There are about 200 species in the malaria parasite genus, and five species regularly infect humans, while other species infect birds, reptiles, rodents and various primates. P. falciparum , P. vivax , P. ovale , and P. malariae together account for nearly all human infections with Plasmodium falciparum species; Plasmodium falciparum accounts for the overwhelming majority of malaria deaths. Malaria symptoms typically include fever, fatigue, vomiting and headache. In severe cases, it can cause jaundice, seizures, coma, or death.

Malaria is most commonly transmitted by infected female Anopheles mosquitoes. Mosquito bites transfer parasites from the mosquito's saliva into the human blood. That is, during Plasmodium falciparum infection, female mosquitoes inject small amounts of sporozoites (~10-100) into the skin, which then travel to the liver and invade hepatocytes (Crompton et al. (Crompton et al. 2014) Annu Rev Immunol 32, 157-187). In hepatocytes, sporozoites reproduce asexually (schizogony), producing thousands of merozoites. They infect new red blood cells and begin a series of cycles of asexual growth (hematopoiesis) that produce 8 to 24 new infectious cysts, at which point the cells rupture and the infective cycle begins anew. Other cysts differentiate into immature gametocytes, the precursors of male and female gametes. When a fertilized mosquito bites an infected person, the germ cells are absorbed into the blood and mature in the mosquito's intestines.

The male and female germ cells fuse to form a zygote, a modified zygote. The kinetochore migrates to the insect's salivary glands and differentiates into a new sporozoite ready to infect a new vertebrate host.

Although sporozoites are not associated with clinical symptoms, this is when parasite numbers in the host are low and their eradication can completely eliminate the infection. Therefore, vaccines that successfully protect against the sporozoal and liver stages of the Plasmodium falciparum parasite can prevent malaria infection and transmission, making these stages the main target of current malaria vaccine candidates. Therefore, subunit vaccines based on circumsporozoite proteins (CSP), such as RTS,S, are at the center of malaria vaccine efforts.

The malaria parasite circosporozoite protein (CSP) is an approximately 42 kD soluble protein that can be easily produced using an E. coli expression system. CSP is a secreted protein of the sporozoite stage of the malaria parasite. CSP forms a dense membrane on the surface of the parasite and has been hypothesized to mediate many of the initial interactions between the sporozoite and the two hosts (Menard R., 2000, Microbes Infect. 2:633-642; Sinnis P. and Nardin E., 2002 , Sporozoite antigens: biology and immunology of the circumsporozoite protein and thrombospondin related anonymous protein. In Malaria Immunology. P. Perlmann and M. Troye-Blomberg, editors. S. Karger AG, Basel, Switzerland. 70-96). The structure and function of CSP are highly conserved across diverse malaria strains that infect humans, non-human primates, and rodents. The amino acid sequence of CSP contains an immunodominant central repeat region, which varies across Plasmodium falciparum species (NANP-repeat region in the case of Plasmodium falciparum). Flanking the repeat are two conserved motifs at the N- and C-termini: region I and type I thrombospondin repeat (TSR), which are 5-aa sequences at the N terminus of the repeat. There is a known cell-attachment motif C-terminus to the repeat referred to. These conserved motifs are implicated in protein processing as the parasite moves from mosquito to mammalian vector.

CSP is known to play an important role in the movement of sporozoites from the midgut wall of infected mosquitoes to the mosquito salivary glands. Additionally, the N-terminus of CSP is involved in hepatocyte binding in mammalian hosts, and the central repeat region of CSP initially promotes parasite binding. Hepatocyte surface proteolytic cleavage of N-terminal region 1 exposes the C-terminal attachment domain, priming the parasite for invasion into the liver (Coppi et al. (2005) J Exp Med 201, 27 -33).

Currently, the main malaria vaccine is RTS,S/AS01 (trade name Mosquirix), a recombinant protein-based malaria vaccine. RTS,S is a hybrid protein particle formulated with a multi-component adjuvant called AS01. The RTS,S vaccine antigen consists of 19 NANP amino acid repeat units fused to the hepatitis B virus S protein followed by the complete C-terminal domain minus the GPI anchor of the CS antigen. The S protein matches the surface antigen of hepatitis B virus (HBsAg). Approved for use by European regulators in July 2015, the vaccine is not only the world's first licensed malaria vaccine, but also the first vaccine licensed for use against any type of parasitic disease. Although RTS,S causes the production of antibodies that can prevent invasion of hepatocytes and further triggers a cellular response that allows destruction of infected hepatocytes, RTS,S presented problems in testing due to its poor immunogenicity. RTS,S attempted to circumvent this effect by fusing the surface antigen and protein of hepatitis B to create a more potent and immunogenic vaccine. Additionally, the RTS,S protein is available in the potent adjuvant AS01, a liposome-based formulation containing the immunostimulants monophosphoryl lipid A (MPL, Toll-like receptor 4 agonist) and QS-21 (a derivative of Quill A). It had to be formulated in However, the efficacy level of RTS,S/AS01 was lower than expected. In particular, the protective effect of the vaccine is known to decline rapidly after vaccination. Although overall efficacy appears to decrease over time, the effect of the booster dose was positive. After four years, there was a 36% decrease in children who received three shots and a booster dose. Without booster doses, efficacy against severe malaria was reduced to negligible levels. This vaccine has not been shown to be effective in infants. Three doses of the vaccine plus a booster dose reduced the risk of a clinical episode by 26% over 3 years, but did not provide significant protection against severe malaria.

Additionally, another factor that has complicated the development of these vaccines is the difficulty in identifying strong protective correlates. Antibodies have been shown to inhibit sporozoite invasion of hepatocytes in in vitro functional assays, but their role in protection of malaria-vaccinated individuals remains unclear.

Therefore, there is still a need for more potent malaria vaccines that prevent malaria infection and transmission. Moreover, there is still a need for specific antibodies, especially antibodies that potently inhibit sporozoite invasion and liver stage parasite proliferation in vivo.

In view of the above, the aim of the present invention is to overcome the shortcomings of current malaria antibodies and vaccines outlined above. In particular, the object of the present invention is to provide a malaria vaccine that is superior to the malaria vaccines of the prior art, for example due to its efficacy. It is also an object of the present invention to provide an antibody that is superior to prior art malaria antibodies, for example by strongly inhibiting sporozoite invasion and liver stage parasite proliferation in vivo.

The object of the present invention is achieved by the subject matter described below and the appended claims.

Although the invention is described in detail below, it should be understood that the invention is not limited as the specific methodologies, protocols and reagents described herein may vary. Additionally, it should be understood that the terminology used herein is not intended to limit the scope of the invention, which will be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains.

In the following, elements of the present invention will be described. Although these elements are listed with specific embodiments, it should be understood that they may be combined in any way and in any number to create additional embodiments. The various described examples and preferred embodiments should not be construed to limit the invention to only the explicitly described embodiments. This description should be understood to support and include embodiments that combine the explicitly described embodiments with any number of disclosed and/or preferred elements. Additionally, any substitutions and combinations of any elements described in this application are to be considered as disclosed by the description of this application unless the context otherwise indicates.

Throughout the specification and claims that follow, unless the context otherwise requires, the terms "comprise" and variations such as "comprises" and "comprising" refer to the referenced elements, It will be understood to mean suggesting an integer or step but not excluding other configurations, integers or steps not mentioned. The term “consist of” is a specific embodiment of the term “comprise” and excludes other elements, integers or steps not mentioned herein. In the context of the present invention, the term “comprise” includes the term “consist of”. Accordingly, the term "comprising" includes "including" and "consisting," for example, a composition "comprising" X may consist only of Can contain additional things like +Y.

In the context of describing the invention (and especially in relation to the claims), the terms “a” and “an” and “the” and similar references shall be referred to in the singular and plural unless otherwise indicated herein or clearly contradictory from the context. It should be interpreted as inclusive of all. References to ranges of values herein are intended solely to serve as a shorthand method of referring individually to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

The word “substantially” does not exclude “completely,” for example, a composition that is “substantially free” from Y may be completely free of Y. If necessary, the word “substantially” may be omitted from the definition of the invention.

The term “about” in relation to a numerical value x means x ± 10%.

As used herein, the term "disease" is intended generally as synonyms, and "disorder" and "condition" (from medical condition) in that both reflect either an abnormal state of the human or animal body or a part of the body that impairs its normal functioning. It is used interchangeably with the term, and generally indicates signs and symptoms separately, and causes a decrease in the lifespan and/or quality of life of humans or animals.

As used herein, reference to “treatment” of a subject or patient is intended to include prevention, prophylaxis, amelioration, and therapy. The terms “subject” or “patient” are used interchangeably herein to refer to any mammal, including humans. Examples of subjects include humans, cattle, dogs, cats, horses, goats, sheep, pigs, and rabbits. Preferably, the subject or patient is human.

As used herein, the terms “peptide”, “polypeptide” and “protein” are used interchangeably. The terms “peptide,” “polypeptide,” and “protein” and variations of these terms typically refer to molecules, particularly peptides, oligopeptides, polypeptides, or modified peptide bonds, such as in the case of normal peptide bonds or, for example, isosteric peptides. Refers to a protein, such as a fusion protein, containing at least two amino acids interconnected by peptide bonds; for example, a "typical" peptide, polypeptide, or protein is usually defined by the genetic code interconnected by normal peptide bonds. It consists of amino acids selected from 20 amino acids. A peptide, polypeptide or protein may be composed of L-amino acids and/or D-amino acids. Preferably, the peptide, polypeptide or protein consists (entirely) of L-amino acids or (entirely) of D-amino acids. In particular, the terms "peptide", "polypeptide", and "protein" also include "peptidomimetics", which are defined as peptide analogs that contain non-peptide structural elements, and peptides that mimic the biological action of the natural parent peptide ( ) can imitate or antagonize. Peptidomimetics lack typical peptide characteristics, such as peptide bonds that are susceptible to enzymatic cleavage. In particular, the peptide, polypeptide or protein may include, in addition to these amino acids, amino acids other than the 20 amino acids defined by the genetic code, or may consist of amino acids other than the 20 amino acids defined by the genetic code. In particular, the peptides, polypeptides or proteins in the context of the present invention may equally consist of amino acids modified by natural processes or chemical processes, such as post-translational maturation processes well known to those skilled in the art. . These modifications are described in detail in the literature. These modifications may occur anywhere in the polypeptide, i.e., in the peptide backbone, amino acid chain, or even at the carboxy- or amino-terminus. In particular, the peptide or polypeptide may be branched or may be branched or unbranched cyclized following ubiquitination. This type of modification may be the result of natural or synthetic post-translational processes well known to those skilled in the art (Proteins Structure and Molecular Properties (1993) 2nd Ed., T. E. Creighton, New York; Post -translational Covalent Modifications of Proteins (1983) B. C. Johnson, Ed., Academic Press, New York ; Seifter et al. (1990) Analysis for protein modifications and nonprotein cofactors, Meth. Enzymol. 182: 626-646 and Rattan et al. , (1992) Protein Synthesis: Post-translational Modifications and Aging, Ann NY Acad Sci, 663: 48-62). Accordingly, the terms “peptide”, “polypeptide”, “protein” preferably include lipopeptides, lipoproteins, glycopeptides, glycoproteins, etc.

As used herein, “(poly)peptide” includes a single chain of amino acid monomers linked by peptide bonds as described above. As used herein, “protein” means one or more, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (poly) peptides, i.e. peptide bonds as described above. It contains one or more amino acid monomer chains linked by. Preferably, the protein according to the invention comprises 1, 2, 3 or 4 polypeptides.

As used herein, the term “recombinant protein” refers to any protein that is manufactured, expressed, produced or isolated by recombinant methods, especially those that do not occur in nature.

As used herein, the term “antibody” refers to whole antibodies, antibody fragments, especially antigen-binding fragments, human antibodies, chimeric antibodies, humanized antibodies, recombinant antibodies and genetically engineered antibodies (variant or It includes various types of antibodies, including but not limited to mutant antibodies). Human antibodies and monoclonal antibodies are preferred, particularly human monoclonal antibodies, especially recombinant human monoclonal antibodies.

Human antibodies are well known in the art (van Dijk, MA, and van de Winkel, JG, Curr. Opin. Chem. Biol. 5 (2001) 368-374). In particular, human antibodies can also be produced in transgenic animals (e.g., mice) that, upon immunization, can produce a full repertoire or selection of human antibodies in the absence of endogenous immunoglobulins. Transfer of the human germline immunoglobulin gene array in these germline mutant mice will result in the production of human antibodies upon antigen challenge (e.g., Jakobovits, A., et al., Proc. Natl. Acad. Sci. USA 90 (1993 ) 2551-2555; Jakobovits, A., et al., Nature 362 (1993) 255-258; Bruggemann, M., et al., Year Immunol. 7 (1993) 3340). Human antibodies can also be produced from phage display libraries (Hoogenboom, HR, and Winter, G., J. Mol. Biol. 227 (1992) 381-388; Marks, JD, et al., J. Mol. Biol. 222 (1991 ) 581-597). The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy , Alan R. Liss, p. 77 (1985); and Boerner, P., et al. , J. Immunol. 147 (1991) 86-95). Most preferably, the human monoclonal antibodies are Traggiai E, Becker S, Subbarao K, Kolesnikova L, Uematsu Y, Gismondo MR, Murphy BR, Rappuoli R, Lanzavecchia A. (2004): An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat Med. Prepared using improved EBV-B cell immortalization as described in 10(8):871-5. As used herein, the term “human antibody” also includes antibodies that have been modified, for example in the variable region, to produce properties according to the invention as described herein. As used herein, the term “variable region” (variable region of a light chain (VL), variable region of a heavy chain (VH)) refers to the light and heavy chain pairs, respectively, that are directly involved in binding an antibody to an antigen.

Antibodies of the invention may be of any isotype (e.g., IgA, IgG, IgM, i.e., α, γ or μ heavy chain), but will preferably be IgG. Within the IgG isotype, antibodies can be of the IgG1, IgG2, IgG3 or IgG4 subclass, with IgG1 being preferred. Antibodies of the invention may have κ or λ light chains.

Preferably, the antibody or antigen-binding fragment thereof according to the invention is a purified antibody, single chain antibody, Fab, Fab', F(ab')2, Fv or scFv.

Therefore, the antibody of the present invention may preferably be a human antibody, monoclonal antibody, human monoclonal antibody, recombinant antibody, or purified antibody. The invention also provides fragments of the antibodies of the invention, particularly fragments that retain the antigen-binding activity of the antibody. Such fragments include, but are not limited to, single chain antibodies, Fab, Fab', F(ab')2, Fv or scFv. Although the specification, including the claims, may in some places explicitly refer to antigen-binding fragment(s), antibody fragment(s), variant(s) and/or derivative(s) of an antibody, the term "antibody" It is understood to include all categories of antibodies, namely antigen-binding fragment(s), antibody fragment(s), variant(s) and derivative(s) of antibodies.

As used herein, the terms “antigen binding fragment,” “fragment,” and “antibody fragment” are used interchangeably to refer to any fragment of an antibody of the invention that retains the antigen-binding activity of the antibody. Examples of antibody fragments include, but are not limited to, single chain antibodies, Fab, Fab', F(ab') ₂ , Fv, or scFv. Fragments of antibodies of the invention can be obtained from antibodies by methods involving cleavage of disulfide bonds by chemical reduction and/or digestion by enzymes such as pepsin or papain. Alternatively, fragments of antibodies can be obtained by cloning and expressing portions of the heavy or light chain sequences. Antibody “fragments” include Fab, Fab', F(ab')2 and Fv fragments. The invention also includes single-chain Fv fragments (single-chain Fv, scFv) derived from the heavy and light chains of the antibodies of the invention. For example, the invention includes scFvs comprising CDRs from antibodies of the invention. Heavy or light chain monomers and dimers, single domain heavy chain antibodies, single domain light chain antibodies as well as single chain antibodies, such as single chain Fvs in which the heavy and light chain variable domains are linked by a peptide linker.

Antibody fragments of the invention may confer monovalent or multivalent interactions and may be incorporated into a variety of structures as described above. For example, scFv molecules can be synthesized to produce a trivalent “triabody” or a tetravalent “tetrabody”. The scFv molecule may contain domains of the Fc region to create a bivalent minibody. Additionally, the sequence of the present invention may be a component of a multispecific molecule in which the sequence of the present invention targets an epitope of the present invention and other regions of the molecule bind to other targets. Exemplary molecules include, but are not limited to, bispecific Fab2, trispecific Fab3, bispecific scFv, and diabodies (Holliger and Hudson, 2005, Nature Biotechnology 9: 1126-1136).

Antibodies according to the invention may be provided in purified form. Typically, the antibody will be present in a composition that is substantially free of other polypeptides, for example, less than 90% (by weight) of the composition consists of other polypeptides.

Antibodies according to the invention may be immunogenic in human and/or non-human (or xenogeneic) hosts, for example in mice. For example, an antibody may have an idiotope that is immunogenic in non-human hosts but not in human hosts. Antibodies of the invention for human use include those that cannot be easily isolated from hosts such as mouse, goat, rabbit, rat, non-primate mammal, etc. and generally cannot be obtained from humanized or xeno-mouse.

As used herein, a “neutralizing antibody” is one that is capable of neutralizing, i.e., preventing, inhibiting, reducing, interfering with, or interfering with the ability of a pathogen to initiate and/or perpetuate infection in a host. The terms “neutralizing antibody” and “neutralizing antibody” or “neutralizing antibodies” are used interchangeably herein. These antibodies can be used alone or in combination as prophylactic or therapeutic agents, depending on the appropriate formulation, in the context of active vaccination, as diagnostic tools or as production tools described herein.

As used herein, the terms “nucleic acid,” “nucleic acid molecule,” and “polynucleotide” are used interchangeably and are intended to include DNA molecules and RNA molecules. The nucleic acid molecule may be single-stranded or double-stranded, but is preferably double-stranded DNA.

As used herein, the terms “cell,” “cell line,” and “cell culture” are used interchangeably and all such designations include progeny. Accordingly, the terms “transformant” and “transformed cell” include the primary cell of interest and cultures derived therefrom, regardless of the number of transfers. It is also understood that all offspring may not be exactly identical in DNA content due to intentional or unintentional mutations. Mutant progeny that have the same function or biological activity as screened for in the originally transformed cell are included. If a separate designation is intended, this will become clear from the context.

Dosage is often expressed in relation to body weight. Therefore, a dose expressed in [g, mg, or other units]/kg (or g, mg, etc.) is usually "per kg (or g, mg, etc.) of body weight" even if the term "body weight" is not explicitly mentioned. Indicates [g, mg or other units].

The term “binding”, especially “specifically binding” and similar references do not include non-specific fixation.

As used herein, the term “vaccine” is understood to be a prophylactic or therapeutic substance that typically presents at least one antigen, preferably an immunogen. The antigen or immunogen may be derived from any material suitable for vaccination. For example, the antigen or immunogen may be derived from a pathogen such as a bacterium, viral particle or protozoa, parasite, etc., or from a tumor or cancerous tissue. Antigens or immunogens typically stimulate the body's adaptive immune system so that they can provide an adaptive immune response. In particular, an “antigen” or “immunogen” can typically be recognized by the immune system, preferably the adaptive immune system, e.g. by forming antibodies and/or antigen-specific T cells as part of an adaptive immune response. Refers to a substance that can induce a specific immune response. Typically, the antigen may be or comprise a peptide or protein that can be presented to T-cells by MHC.

As used herein, a “sequence variant” (also referred to as a “variant”) refers to any change in a reference sequence, whereby the reference sequence is referred to in the “Sequence and SEQ ID Number Table” (Sequence Listing) , i.e. any sequence listed in SEQ ID NO: 1 to SEQ ID NO: 332. Accordingly, the term “sequence variant” includes nucleotide sequence variants and amino acid sequence variants. In particular, in a “sequence variant” the functionality (of the reference sequence) is preserved, i.e. the sequence variant is functional (also referred to as a “functional sequence variant”). Sequence variants typically retain the biological function of, for example, an antibody or antigen/immunogen. In the context of the present invention, this retained biological function is preferably the binding of an antibody to Plasmodium falciparum sporozoites, in particular the Plasmodium circus sporozoite protein (CSP), or the ability of the peptide/protein to induce an immune response, in particular antibody production. .

Preferred sequence variants are therefore at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% % or at least 99% sequence identity. As used herein, the phrase “at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or a functional sequence variant having at least 99% sequence identity” means that (i) the sequence variant is functional as described herein and (ii) the higher the % sequence identity, the more preferred the sequence variant. In other words, the phrase "at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least “Functional sequence variant with 99% sequence identity” means in particular that the functional sequence variant has at least 70% sequence identity, preferably at least 75% sequence identity, preferably at least 80% sequence identity, with respect to the respective reference sequence, More preferably at least 85% sequence identity, more preferably at least 88% sequence identity, even more preferably at least 90% sequence identity, even more preferably at least 92% sequence identity, even more preferably at least 95% sequence identity, more preferably at least 96% sequence identity, particularly preferably at least 97% sequence identity, particularly preferably at least 98% sequence identity, and most preferably at least 99% sequence identity. It means having the same identity.

Sequence identity is usually calculated relative to the entire length of the reference sequence (i.e., the sequence cited in the specification). Percent identities referred to herein are, for example, NCBI (the National Center for Biotechnology Information; http://www.ncbi.nlm.nih.gov/) [Blosum 62 matrix; This can be determined using BLAST using default parameters specified by gap open penalty=11 and gap extension penalty=1.

A nucleotide “sequence variant” (i.e., a “sequence variant” of a nucleotide sequence), with respect to a nucleotide sequence, is one in which one or more nucleotides are deleted or substituted in the reference sequence or in which one or more nucleotides are inserted into the sequence of the reference nucleotide sequence. It has a modified sequence. Nucleotides are referred to herein by their standard one-letter names (A, C, G or T). Due to modifications of the genetic code, “sequence variants” of a nucleic acid (nucleotide) sequence may or may not result in changes in the respective reference amino acid sequence, i.e., a “sequence variant” of the respective amino acid sequence. Preferred sequence variants are those nucleotide sequence variants that do not result in amino acid sequence variants (silent mutations), but other non-silent mutations are also within range, in particular the mutant nucleotide sequence is at least 70% identical to the reference sequence, and preferably results in an amino acid sequence that is at least 80% identical, more preferably at least 90% identical, even more preferably at least 95% identical, and particularly preferably at least 99% identical to the reference sequence.

With respect to amino acids, an amino acid "sequence variant" (i.e., a "sequence variant" of an amino acid sequence) is one in which one or more amino acids are deleted or substituted in the reference sequence, or in which one or more amino acids are inserted into the sequence of the reference amino acid sequence. It has a modified sequence. As a result of the modification, the amino acid sequence variant is at least 70% identical to the reference sequence, preferably at least 80% identical to the reference sequence, more preferably at least 90% identical, and even more preferably at least 95% identical, Particularly preferably it has an amino acid sequence that is at least 99% identical to the reference sequence. A variant sequence that is at least 90% identical has no more than 10 modifications, i.e., a combination of deletions, insertions, or substitutions, per 100 amino acids of the reference sequence.

With respect to a peptide/protein, a “linear sequence” or “sequence” is the order of amino acids in a peptide/protein in the amino to carboxyl terminus direction such that residues adjacent to each other in the sequence are consecutive in the primary structure of the peptide/protein.

Although it is possible to have non-conservative amino acid substitutions in a "sequence variant," a substitution in a "sequence variant" means that the substituted amino acid has similar structural and/or chemical properties to the corresponding substituted amino acid (i.e., the amino acid in the original sequence for which it was substituted). It is preferable that it is a conservative amino acid substitution. By way of example, conservative amino acid substitutions include replacing one aliphatic or hydrophobic amino acid, such as alanine, valine, leucine, and isoleucine, with another; Substituting one hydroxyl-containing amino acid, such as serine and threonine, for another; Substituting one acidic residue, such as glutamic acid or aspartic acid, for another; replacing one amide-containing residue, such as asparagine and glutamine, with another; Replacing one aromatic residue, such as phenylalanine and tyrosine, with another; replacing one basic residue, such as lysine, arginine, and histidine, with another; and replacing one small amino acid, such as alanine, serine, threonine, methionine, and glycine, with another.

Amino acid sequence insertions include intrasequence insertions of one or multiple amino acid residues as well as amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing hundreds or more residues. Examples of terminal insertions include fusion to the N- or C-terminus of an amino acid sequence to a reporter molecule or enzyme.

Importantly, sequence variants are generally functional sequence variants, i.e. modifications in a sequence variant do not abolish the functionality of the respective reference sequence as described above. Instructions for determining which nucleotides and amino acid residues can be respectively substituted, inserted, or deleted without losing such functionality are found using computer programs well known in the art.

As used herein, a nucleic acid sequence or amino acid sequence “derived from” a designated nucleic acid, peptide, polypeptide, or protein refers to the origin of the nucleic acid, peptide, polypeptide, or protein. Preferably, a nucleic acid sequence or amino acid sequence derived from a particular sequence has an amino acid sequence that is essentially identical to that sequence or a portion thereof, and "essentially identical" derived therefrom includes sequence variants as defined above. Preferably, the nucleic acid sequence or amino acid sequence derived from a particular peptide or protein is derived from a corresponding domain of the particular peptide or protein. Hereby, “corresponding” refers specifically to the same function. For example, an “extracellular domain” corresponds to a different “extracellular domain” (of another protein), or a “transmembrane domain” corresponds to a different “transmembrane domain” (of another protein). “Corresponding” portions of peptides, proteins and nucleic acids can be readily identified by those skilled in the art. Likewise, a sequence that is “derived from” another sequence can generally be readily identified by a person of ordinary skill in the art as having its origin in that sequence.

Preferably, the nucleic acid sequence or amino acid sequence derived from another nucleic acid, peptide, polypeptide or protein may be identical to the starting nucleic acid, peptide, polypeptide or protein (from which it is derived). However, a nucleic acid sequence or amino acid sequence derived from another nucleic acid, peptide, polypeptide or protein may also have one or more mutations with respect to the starting nucleic acid, peptide, polypeptide or protein (from which it is derived), especially the other nucleic acid, A nucleic acid sequence or amino acid sequence derived from a peptide, polypeptide or protein may be a functional sequence variant of (derived from) the starting nucleic acid, peptide, polypeptide or protein described above. For example, one or more amino acid residues in a peptide/protein may be substituted for another amino acid residue or insertion or deletion of one or more amino acid residues may occur.

As used herein, the term “mutation” refers to a change in a nucleic acid sequence and/or amino acid sequence compared to a reference sequence, e.g., a corresponding genomic sequence. For example, mutations may be caused by (naturally occurring) somatic mutations, naturally occurring mutations, induced mutations, such as those induced by enzymes, chemicals or radiation, or site-specific mutations, for example compared to the genomic sequence. It may be an acquired mutation (a molecular biological method to create specific, intentional changes in the nucleic acid sequence and/or amino acid sequence). Accordingly, the terms “mutation” or “mutating” will also be understood to include physically making a mutation, for example in a nucleic acid sequence or amino acid sequence. Mutations include substitutions, deletions and insertions of one or more nucleotides or amino acids as well as inversions of several consecutive nucleotides or amino acids. In order to achieve mutations in the amino acid sequence, mutations may be introduced into the nucleotide sequence encoding said amino acid sequence, preferably in order to express the (recombinant) mutated polypeptide. Mutations may occur, for example, by site-directed mutagenesis, by changing the codons of a nucleic acid molecule encoding one amino acid to create a codon encoding a different amino acid, or by synthesizing sequence variants, e.g. This can be achieved by knowing the nucleotide sequence of the nucleic acid molecule and designing the synthesis of a nucleic acid molecule comprising a nucleic acid sequence comprising a nucleotide sequence encoding a polypeptide variant without the need to mutate one or more nucleotides of the nucleic acid molecule.

Several documents are cited throughout this specification. Each document cited herein (including all patents, patent applications, scientific publications, manufacturer's instructions, instructions, etc.), whether supra or infra, is incorporated herein by reference in its entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

It should be understood that the invention may vary in the specific methodologies, protocols, and reagents described herein, but is not limited thereto. Additionally, it should be understood that the terminology used herein is for the purpose of describing specific embodiments and is not intended to limit the scope of the invention, which is to be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains.

The present invention is based, among other discoveries, on the surprising discovery of a very potent antibody that binds to the malaria circosporozoite protein (CSP). In particular, these antibodies were surprisingly found to bind to an epitope of the malaria circosporozoite protein located/between the junction between the N-terminus and the NANP-repeat, close to the functionally important region I. Interestingly, this region is not included in the only currently approved malaria vaccine, RTS,S/AS01.

A peptide comprising or consisting of an amino acid according to SEQ ID NO: 1

In a first aspect, the invention provides a peptide comprising or consisting of an amino acid according to SEQ ID NO: 1:

NPDP

[SEQ ID NO: 1]

This motif can be found in the C-terminus of the malaria parasite circosporozoite protein of region I and at the N-terminus of the NANP-repeat. Surprisingly, antibodies binding to the motif according to SEQ ID NO: 1 were found to be very potent and significantly reduce the liver parasite burden (of Plasmodium spp.) in vivo, suggesting that these antibodies are capable of (i) sporozoite invasion and (ii) It exhibits the ability to strongly inhibit liver stage parasite proliferation in vivo.

all. The peptides according to the invention are capable of generating such potent antibodies, thereby producing, for example, a potent vaccine against malaria resulting in inhibition of (i) sporozoite invasion and (ii) liver stage parasite proliferation in vivo. useful for Thereby, it is possible to prevent and/or treat disease in an individual, as well as suppress the spread of the disease in the population.

Preferably, the peptide according to the invention comprises or consists of an amino acid sequence according to any one of SEQ ID NO: 2 to 5, preferably the peptide comprises an amino acid sequence according to SEQ ID NO: 5.

For example, a peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 2:

NPDPN

[SEQ ID NO: 2]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 3:

NPDPNA

[SEQ ID NO: 3]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 4:

NPDPNAN

[SEQ ID NO: 4]

More preferably, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 5:

NPDPNANP

[SEQ ID NO: 5]

This peptide according to SEQ ID NO: 5 comprises, in addition to the motif according to SEQ ID NO: 1, a first “NANP”-sequence (i.e. the very N-terminal part of the NANP-repeat).

Additionally, the peptide according to the present invention may preferably comprise or consist of an amino acid sequence according to any one of SEQ ID NOs: 6 to 22.

For example, a peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 6:

NPDPNANPN

[SEQ ID NO: 6]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 7:

GNPDPNANP

[SEQ ID NO: 7]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 8:

GNDPPNANPN

[SEQ ID NO: 8]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 9:

DGNPDPNANP

[SEQ ID NO: 9]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 10:

NPDPNANPNK

[SEQ ID NO: 10]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 11:

DGNPDPNANPN

[SEQ ID NO: 11]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 12:

GNPDPNANPNK

[SEQ ID NO: 12]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 13:

DGNPDPNANPNK

[SEQ ID NO: 13]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 14:

ADGNPDPNANPN

[SEQ ID NO: 14]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 15:

QPADGNPDPNANPNK

[SEQ ID NO: 15]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 16:

ADGNPDPNANPNK

[SEQ ID NO: 16]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 17:

PADGNPDPNANPNK

[SEQ ID NO: 17]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 18:

ADGNPDPNANPNKN

[SEQ ID NO: 18]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 19:

PADGNPDPNANPNKN

[SEQ ID NO: 19]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 20:

QPADGNPDPNANPNKN

[SEQ ID NO: 20]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 21:

PADGNPDPNANPNKNN

[SEQ ID NO: 21]

For example, the peptide according to the invention preferably comprises or consists of an amino acid sequence according to SEQ ID NO: 22:

QPADGNPDPNANPNKNN

[SEQ ID NO: 22]

More preferably, the peptide according to the invention is according to SEQ ID NO: 23 or at least 72%, preferably at least 77%, more preferably at least 83%, even more preferably at least 88%, Most preferably it comprises or consists of amino acid sequences that share at least 94% sequence identity.

KQPADGNPDPNANPNKNN

[SEQ ID NO: 23]

In general, the peptide according to the invention is preferably a fragment of the Plasmodium falciparum circosporozoite protein (CSP), more preferably a fragment of the Plasmodium falciparum circosporozoite protein, or, preferably, (according to the invention at least 70%, preferably at least 80% (over the entire length of the peptide) of a Plasmodium falciparum sporozoite protein and, more preferably, of a fragment of a Plasmodium falciparum sporozoite protein (over the entire length of the peptide according to the invention) , more preferably at least 90%, even more preferably at least 95%, and most preferably at least 98%. In other words, the peptide preferably consists of a fragment of the Plasmodium circus sporozoite protein (CSP), more preferably a fragment of the Plasmodium falciparum sporozoite protein, or a (functional) sequence variant thereof as described herein. This means that particularly preferred peptides (i) comprise a “core” motif according to any one of SEQ ID NOs: 1 to 23 as described above, wherein said core motif is particularly preferably a core motif according to SEQ ID NOs: 1 or 5, and (ii) ) The “outer” peptide of the core motif is still a sequence variant of the CSP described herein. For this purpose, sequence identity is calculated over the entire length of the peptide compared to the (corresponding) CSP fragment as a reference sequence. A preferred CSP reference sequence is the amino acid sequence according to SEQ ID NO:24. Therefore, the fragment of the malaria parasite circosporozoite protein (mentioned above) is preferably the fragment of SEQ ID NO: 24. As mentioned above, the fragment of the malaria parasite (P. falciparum) circosporozoite protein (CSP) preferably has at least 8 or 10 amino acids, preferably at least 15 amino acids, preferably at least 20 amino acids, More preferably at least 25 amino acids, more preferably at least 30 amino acids, more preferably at least 40 amino acids, even more preferably at least 50 amino acids, even more preferably at least 75 amino acids, even more preferably at least It has a length of 100 amino acids, more preferably at least 150 amino acids, even more preferably at least 200 amino acids, and most preferably at least 300 amino acids.

Preferably, the peptide according to the invention has at most 380 amino acids, preferably at most 350 amino acids, preferably at most 320 amino acids, more preferably at most 300 amino acids, more preferably at most 275 amino acids. No more than 250 amino acids, more preferably no more than 250 amino acids, even more preferably no more than 225 amino acids, even more preferably no more than 200 amino acids, even more preferably no more than 200 amino acids, even more preferably no more than 175 amino acids. The following amino acids, more preferably 150 or fewer amino acids, even more preferably 125 or fewer amino acids, even more preferably 100 or fewer amino acids, particularly preferably 75 or fewer amino acids, and most preferably It has a length of 50 amino acids or less.

More preferably, the peptide according to the invention has a length of 4 to 380 amino acids, preferably the peptide has a length of 5 to 350 amino acids, preferably the peptide has a length of 5 to 300 amino acids, preferably Preferably the peptide has a length of 5 to 250 amino acids, more preferably the peptide has a length of 5 to 200 amino acids, more preferably the peptide has a length of 5 to 150 amino acids, and even more preferably the peptide has a length of The peptide has a length of 5 to 100 amino acids, even more preferably the peptide has a length of 6 to 80 amino acids, even more preferably the peptide has a length of 7 to 70 amino acids, even more preferably the peptide has a length of 8 to 80 amino acids. The peptide has a length of 60 amino acids, more preferably the peptide has a length of 9 to 50 amino acids, even more preferably the peptide has a length of 10 to 40 amino acids, and even more preferably the peptide has a length of 11 amino acids. The peptide has a length of between 12 and 25 amino acids, and most preferably the peptide has a length of between 12 and 25 amino acids.

According to any of the preceding claims, the peptide is a recombinant peptide. Recombinant peptides are peptides that do not occur in nature. For example, a peptide can be modified as described herein, and the resulting modified peptide is a peptide that does not occur in nature. This can be achieved by non-natural (or synthetic) modifications or modifications that do not occur naturally in the peptide according to the invention. Alternatively or additionally, recombinant peptides may also differ in length from naturally occurring peptides.

Moreover, the peptide preferably contains one or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly one or (ii) one or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly two or (ii) two or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly 3 or (ii) 3 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 4 or (ii) 4 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly 5 or (ii) 5 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 6 or (ii) 6 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention contains (i) exactly 7 or (ii) 7 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 8 or (ii) 8 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly 9 or (ii) 9 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 10 or (ii) 10 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly 11 or (ii) 11 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 12 or (ii) 12 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly 13 or (ii) 13 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 14 or (ii) 14 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly 15 or (ii) 15 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 16 or (ii) 16 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly 17 or (ii) 17 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 18 or (ii) 18 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). Preferably, the peptide according to the invention comprises (i) exactly 19 or (ii) 19 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP). It is also preferred that the peptide according to the present invention contains (i) exactly 20 or (ii) 20 or more mutations compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP).

Preferably, the peptide according to the invention has 1, 2, 3 compared to the corresponding reference fragment of the malaria parasite circosporozoite protein (CSP), more preferably compared to the corresponding reference fragment of SEQ ID NO: 24. , contains 4 or 5 mutations.

The peptides according to the invention are preferably used for the prevention and/or treatment of malaria as described herein. In other words, the peptide according to the invention is preferably used for the manufacture of a medicament, preferably for the prevention and/or treatment of malaria as described herein.

Proteins, virus-like particles and protein nanoparticles comprising peptides according to the invention

In a further aspect the invention provides a protein comprising a peptide according to the invention. Accordingly, proteins may be composed of peptides according to the invention. However, it is preferred that the protein comprises (i) a peptide according to the invention and (ii) preferably additional amino acid sequences which provide synergistic and/or additional functionality to the protein. In other words, these additional amino acid sequences may enhance the functionality of the peptide (such as the immunogen/antigen), preferably in addition to the functionality of the peptide (such as the immunogen/antigen) acting synergistically with the functionality of the peptide (such as the immunogen/antigen). Non-limiting examples of such functionality include (i) targeting, e.g., as described below, and (ii) immunogenicity, e.g., as described below.

For this purpose, it is preferable that the protein according to the present invention is a fusion protein. Fusion proteins typically contain two or more distinct functionalities. Thus, a fusion protein generally comprises “parts” from different sources, e.g. a fusion protein is a fusion protein comprising different proteins/peptides encoded by at least two different genes or parts of (different) genes. . Accordingly, fusion proteins may also be referred to as “chimeric proteins.” Although fusion proteins typically require complex mutations, such as chromosomal translocations, tandem duplications, or retrotranspositions (e.g. in cancer cells), parts of the coding sequence are derived from two different genes. When generating new coding sequences comprising a recombinant fusion protein (which does not occur in nature) is preferred, although it may occur naturally. Recombinant fusion proteins do not occur naturally in that combination.

For example, the protein according to the present invention may include in addition to the peptide HBsAg or fragments of HBsAg according to the present invention. HBsAg is the surface antigen of hepatitis B virus (HBV).

Hepatitis B virus (HBV) has (i) an envelope containing three associated surface proteins (hepatitis B surface antigen, HBsAg) and lipids and (ii) an icosahedral nucleocapsid that surrounds the viral DNA genome and DNA polymerase. (nucleocapsid). The HBV capsid is formed in the cytosol of infected cells during packaging of the RNA pregenome replication complex and buds during synthesis of the viral DNA genome by reverse transcription of the pregenome in the lumen of the particle. ) gains the ability to arise. The three HBV envelope proteins S-HBsAg, M-HBsAg and L-HBsAg form complex transmembrane folds in the endoplasmic reticulum and form disulfide-linked homo- and heterodimers.

“Fragments” of HBsAg typically have at least 5 amino acids, preferably at least 10 amino acids, preferably at least 15 amino acids, preferably at least 20 amino acids, more preferably at least 25 amino acids, more preferably At least 30 amino acids, more preferably at least 40 amino acids, even more preferably at least 50 amino acids, even more preferably at least 75 amino acids, even more preferably at least 100 amino acids, even more preferably at least 150 amino acids. amino acids, most preferably at least 200 amino acids in length. That is, the longer the fragment, the better.

For example, the fragment of HBsAg may include at least the antigenic loop region of HBsAg. The envelope of the hepatitis B virus consists of three “HBV envelope proteins” (also known as “HBsAg”, “hepatitis B surface antigen”): S protein (also known as “small”, S-HBsAg), M protein (also known as “middle”, M-HBsAg) and L protein (also known as “large”, L-HBsAg). S-HBsAg, M-HBsAg and L-HBsAg correspond to the S protein (S-HBsAg) and share the same C-terminal end (also called the "S domain", 226 amino acids) that is important for virus assembly and infectivity. S-HBsAg, M-HBsAg, and L-HBsAg are synthesized and assembled in the endoplasmic reticulum (ER) and secreted as particles through the Golgi apparatus. The S domain, with both the C-terminus as well as the N-terminus of the S domain exposed to the lumen, contains four predicted transmembrane (TM) domains. Transmembrane domains TM1 and TM2 are both required for cotranslational protein integration into the ER membrane, and transmembrane domains TM3 and TM4 are located in the C-terminal third of the S domain. The “antigenic loop region” of HBsAg is located between the predicted TM3 and TM4 transmembrane domains of the S domain of HBsAg, and the antigenic loop region encompasses amino acids 101–172 of the S domain, containing a total of 226 amino acids (Salisse J. and Sureau C., 2009, Journal of Virology 83: 9321-9328). It is important to note that the determinant of infectivity resides in the antigenic loop region of the HBV envelope protein. In particular, residues 119 to 125 of HBsAg contained the CXXC motif, which proved to be the most important sequence required for the infectivity of HBV and HDV (Jaoude GA, Sureau C, Journal of Virology, 2005;79:10460-6 ).

The protein according to the invention comprises the S domain of HBsAg or a sequence variant thereof described herein. More preferably, the protein according to the invention comprises SEQ ID NO: 319 or a sequence variant thereof as described herein:

MENITSGFLGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQSPTSNHSPTSCPPTCPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLVCPLIPGSSTTSTGPCRTCMTTAQGTSMYPSCCCTKPSDGNCTCIPIPSSWAFGKFLWEWASARFSWLSLLVPFVQWFVGLSPTVWLSVIWMMWYWGPSLYSILSPFLPLLPIFFCL WVYI

(SEQ ID NO: 319)

SEQ ID NO: 319 represents an exemplary amino acid sequence of the S domain of HBsAg.

Preferably, the protein according to the invention further comprises a targeting moiety, such as a targeting peptide. Typically, targeting peptides target a specific location of the protein, e.g., a specific cell type, within the cell or including the nucleus, mitochondria, endoplasmic reticulum (ER), chloroplast, apoplast, peroxisome, and plasma membrane. It is a peptide chain that directs transport to specific areas within the cell. After the protein is transported to a specific location, the targeting peptide can be cleaved from the protein, for example by a signal peptidase. Preferred targeting peptides include antibodies such as scFV and fragments thereof. For example, such antibodies or antibody fragments may be directed to surface molecules of a specific cell type.

For example, the targeting peptide has 1000 or fewer amino acids, preferably 500 or fewer amino acids, more preferably 200 or fewer amino acids, even more preferably 100 or fewer amino acids, even more preferably 80 or fewer amino acids. of amino acids, particularly preferably up to 70 amino acids, most preferably up to 50 amino acids. For example, targeting peptides can be 3 to 70 amino acids in length.

The targeting moiety, in particular the targeting peptide, targets the protein according to the invention to specific cell types. More preferably, the targeting moiety, especially the targeting peptide, targets the protein according to the invention to antigen-presenting cells, such as dendritic cells. Antigen-presenting cells (APCs) typically display antigen complexed with major histocompatibility complexes (MHC) on their surface; refers to a process known as “antigen presentation”. T cells can recognize these complexes using their T cell receptor (TCR). Therefore, APCs process antigens and present them to T-cells. Antigen-presenting cells are essential for an effective adaptive immune response because the functions of both cytotoxic and helper T cells depend on APCs. Antigen presentation allows for the specificity of adaptive immunity and can contribute to immune responses against both intracellular and extracellular pathogens.

Preferably, the targeted APC is a specialized APC. Professional antigen-presenting cells are specialized for presenting antigens to T cells, for example by phagocytosis (macrophages and dendritic cells) or receptor-mediated endocytosis (B cells). They are very efficient at internalizing, processing antigens into peptide fragments and then presenting the peptides bound to MHC class II molecules on their membranes. Preferred examples of APCs to be targeted include macrophages, B cells, and dendritic cells.

Most preferably, the targeted APC is a dendritic cell (DC). Dendritic cells have the broadest range of antigen presentation and are required for activation of naive T cells. DCs present antigens to both helper and cytotoxic T cells. It can also perform cross-presentation, a process of presenting exogenous antigens to cytotoxic T cells on MHC class I molecules. Cross-presentation allows activation of these T cells. Dendritic cells can be recognized by targeting moieties, such as targeting peptides, by specific receptors including DEC-205, Clec9A and Clec12A.

Preferably, the targeting moiety, especially the targeting peptide, targets DEC-205. DEC-205 is a type I cell surface protein expressed by dendritic cells (DC). Targeting of DEC-205 can be achieved by a DEC-205 antibody or fragment thereof, such as anti-DEC-205scFv, e.g., described in Birkholz K. et al., 2010, Blood 116(13):2277-85. (but with the peptide according to the invention as antigen/epitope).

It is also preferred that the targeting moiety, especially the targeting peptide, targets Clec9A. Clec9A is a group V C-type lectin-like receptor (CTLR) that functions as an activating receptor and is expressed on myeloid lineage cells. In humans, this receptor is selectively expressed by BDCA3(+) myeloid dendritic cells (mDCs), which are proposed to be the major human cross-presenting mDCs and the human homolog of murine CD8(+) DCs. It can represent (homologue). Targeting of Clec9A has been described, for example, in Huysamen C. et al., 2008, J. Biol. Chem. 283(24):16693-16701 or in Schreibelt G. et al., 2012, Blood 119(10):2284-92.

Preferably, the targeting moiety, especially the targeting peptide, targets Clec12A. Clec12A (also known as CD371 DCAL-2, MICL or CLL-1) is a 30 kD type II transmembrane protein with an extracellular C-type lectin domain belonging to the C-type lectin family. Targeting of Clec12A has been described, for example, by Hutten T.J.A. et al., 2016, J. Immunol. 197 (7) 2715-2725, which can be achieved by Clec12A antibody or fragment thereof.

Therefore, it is preferred that the targeting moiety, especially the targeting peptide, targets DEC-205, Clec9A and/or Clec12A. Thereby, the protein is typically delivered to dendritic cells, which can then process the protein and present an antigen/immunogen, such as a peptide according to the invention, to trigger an immune response.

Additionally, the targeting moiety, particularly the targeting peptide, preferably targets the protein to hepatocytes. For this purpose, the targeting moiety, in particular the targeting peptide, may comprise an antibody or fragment thereof directed to any specific hepatocyte surface molecule.

It is preferred that the targeting moiety, in particular the targeting peptide, comprises the N-terminal region of the malaria parasite circosporozoite protein, especially the Plasmodium falciparum circosporozoite protein. In this regard, the N-terminal region of the malaria parasite circosporozoite protein extends to any fragment of the N-terminus of CSP (the "N-terminus of CSP" above extends to the central repeat region/NANP-repeat region of CSP; i.e. “N-terminus of CSP” refers to all amino acids N-terminus of the central repeat region/NANP-repeat region of CSP as described herein), or a sequence variant thereof as described herein. The N-terminal fragment of CSP typically has at least 3 amino acids, preferably at least 5 amino acids, more preferably at least 8 amino acids, even more preferably at least 10 amino acids, even more preferably at least 12 amino acids. , particularly preferably at least 15 amino acids and most preferably at least 20 amino acids in length. Preferred fragments and sequence variants thereof provide targeting to hepatocytes. A preferred example of “N-terminus of CSP” is shown in SEQ ID NO: 320:

MMRKLAILSVSSFLFVEALFQEYQCYGSSSNTRVLNELNYDNAGTNLYNELEMNYYGKQENWYSLKKNSRSLGENDDGNNEDNEKLRKPKHKKLKQPADGNPDP

(SEQ ID NO: 320)

Particularly preferably, the N-terminal region of the malaria parasite circosporozoite protein comprises or consists of CSP region I, and in particular the N-terminal region of the malaria parasite circosporozoite protein comprises the amino acid sequence according to SEQ ID NO: 25. Includes or consists of.

The N-terminal region of the malarial parasite circosporozoite protein preferably comprises or consists of the amino acid sequence according to SEQ ID NO: 321 or a sequence variant thereof as described herein:

KKLKQPA

(SEQ ID NO: 321)

It is preferred that the N-terminal region of the malaria parasite circosporozoite protein comprises or consists of the amino acid sequence according to SEQ ID NO: 322 or a sequence variant thereof as described herein:

HKKLKQPAD

(SEQ ID NO: 322)

The N-terminal region of the malarial parasite circosporozoite protein preferably comprises or consists of the amino acid sequence according to SEQ ID NO: 323 or a sequence variant thereof as described herein:

KHKKLKQPADG

(SEQ ID NO: 323)

It is preferred that the N-terminal region of the malaria parasite circosporozoite protein comprises or consists of the amino acid sequence according to SEQ ID NO: 324 or a sequence variant thereof as described herein:

KHKKLKQP

(SEQ ID NO: 324)

The N-terminal region of the malarial parasite circosporozoite protein preferably comprises or consists of the amino acid sequence according to SEQ ID NO: 325 or a sequence variant thereof as described herein:

RKPKHKKLKQP

(SEQ ID NO: 325)

It is preferred that the N-terminal region of the malaria parasite circosporozoite protein comprises or consists of the amino acid sequence according to SEQ ID NO: 326 or a sequence variant thereof as described herein:

PKHKKLKQPADGN

(SEQ ID NO: 326)

It is preferred that the N-terminal region of the malaria parasite circosporozoite protein comprises or consists of the amino acid sequence according to SEQ ID NO: 327 or a sequence variant thereof as described herein:

KPKHKKLKQPADGNP

(SEQ ID NO: 327)

It is preferred that the N-terminal region of the malaria parasite circosporozoite protein comprises or consists of the amino acid sequence according to SEQ ID NO: 328 or a sequence variant thereof as described herein:

RKPKHKKLKQPADGNPD

(SEQ ID NO: 328)

It is preferred that the N-terminal region of the malaria parasite circosporozoite protein comprises or consists of the amino acid sequence according to SEQ ID NO: 329 or a sequence variant thereof as described herein:

NEKLRKPKHKKLKQP

(SEQ ID NO: 329)

The N-terminal region of the malarial parasite circosporozoite protein preferably comprises or consists of the amino acid sequence according to SEQ ID NO: 330 or a sequence variant thereof as described herein:

NEKLRKPKHKKLKQPADG

(SEQ ID NO: 330)

Preferably, the protein according to the invention further comprises an immunogenic peptide. In general, immunogenic peptides increase the immunogenicity of the peptides according to the invention. For this purpose, the immunogenic peptide is itself immunogenic, i.e. capable of eliciting an immune response. For example, the immunogenic peptide may comprise an antigen/immunogen distinct from the peptide according to the invention, for example HBsAg as described above. Many immunogenic peptides are known in the art. In addition, it is well known to those skilled in the art how immunogenic peptides can be designed, for example, as described in Flower D.R., 2013, Nature Chemical Biology 9(12): 749-753: Designing immunogenic peptides. It is known.

The protein according to the present invention may further include a linker sequence known in the art to which the present invention pertains, such as a “GS-linker”.

The protein according to the invention preferably has at least 20 amino acids, preferably at least 50 amino acids, preferably at least 60 amino acids, more preferably at least 70 amino acids, more preferably at least 80 amino acids, and more preferably at least 80 amino acids. Preferably at least 90 amino acids, even more preferably at least 100 amino acids, even more preferably at least 150 amino acids, even more preferably at least 200 amino acids, even more preferably at least 250 amino acids, even more preferably It has a length of at least 300 amino acids, most preferably at least 350 or at least 400 amino acids.

In a further aspect, the invention also provides a virus-like particle comprising a peptide according to the invention described herein or a protein according to the invention described herein.

As used herein, “virus-like particle” (also referred to as “VLP”) refers specifically to a non-replicating, viral shell derived from any of several viruses. VLPs generally consist of one or more viral proteins, such as, but not limited to, proteins referred to as capsid, coat, shell, surface and/or envelope proteins, or particle-forming polypeptides derived from these proteins. VLPs can be formed spontaneously upon recombinant expression of proteins in an appropriate expression system. Methods for generating specific VLPs are known in the art to which the present invention pertains.

The presence of VLPs after recombinant expression of viral proteins can be detected using conventional techniques known in the art, such as electron microscopy, biophysical characterization, etc. Additionally, VLPs can be separated by known techniques, such as density gradient centrifugation, and identified by characteristic density banding. For example, Baker et al. (1991) Biophys. J. 60: 1445-1456; and Hagensee et al. (1994) J. Viral. 68:4503-4505; Vincente, J Invertebr Pathol., 2011; Schneider-Ohrum and Ross, Curr. Top. Microbial. Immunol., 354: 53073, 2012.

For example, when HBsAg or other viral proteins are present in sufficient concentrations, virus-like particles spontaneously assemble without DNA, producing non-infectious immunogenic structures. Co-administration allows activation of the immune system and increases antibody responses to the peptides according to the invention.

Accordingly, virus-like particles comprising a peptide according to the invention or a protein according to the invention as described herein are, in particular, virus-like particles comprising a peptide or protein according to the invention comprising SEQ ID NO: 1 (VLP )am. Preferred embodiments of VLPs comprising the peptide according to the invention or the protein according to the invention correspond to preferred embodiments of the peptide according to the invention or the protein according to the invention.

In general, VLPs lack the viral components necessary for viral replication and therefore represent a highly attenuated form of the virus. A VLP may represent a polypeptide (e.g. a peptide according to the invention or a protein according to the invention) that, when administered to a subject, is capable of inducing an immune response against the malaria parasite. Virus-like particles and methods for their production are known and familiar to those skilled in the art, and include human papillomavirus, HIV (Kang et al., Biol. Chem. 380: 353-64 (1999) )), Semliki-Forest virus (Notka et al., Biol. Chem. 380: 341-52 (1999)), human polyomavirus (Goldmann et al., J . Virol. 73: 4465-9 (1999)), rota virus (Jiang et al., Vaccine 17: 1005-13 (1999)), parvovirus (Casal, Biotechnology and Applied Biochemistry, Vol. 29, Part 2, pp 141- 150 (1999)), canine parvovirus (Hurtado et al., J. Viral. 70: 5422-9 (1996)), hepatitis E virus (Li et al., J. Viral. 71: 35 7207-13 (1997)), and viral proteins from several viruses, including Newcastle disease virus, are known to form VLPs. For example, a chimeric VLP comprising a peptide according to the invention may be an HBsAg-based VLP. The formation of such VLPs can be detected by any suitable technique. Examples of suitable techniques known in the art for the detection of VLPs in media include, for example, electron microscopy techniques, dynamic light scattering (DLS), selective chromatographic separation (e.g. ion exchange, hydrophobic interactions and/or size exclusion chromatography separation of VLPs) and density gradient centrifugation.

In a further aspect, the invention also provides protein nanoparticles comprising a peptide according to the invention or a protein according to the invention.

As used herein, “protein nanoparticle” refers to certain multi-subunit, protein-based polyhedral shaped structures. The subunits are each composed of a protein or polypeptide (e.g., a glycosylated polypeptide), and optionally single or multiple features: nucleic acids, prosthetic groups, organic and inorganic compounds. Non-limiting examples of protein nanoparticles include ferritin nanoparticles (e.g. Zhang, Y. Int., incorporated herein by reference. J. Mol. Sci., 12:5406-5421, 2011), encapsulin nanoparticles (e.g., incorporated herein by reference) Sutter et al., Nature Struct. and Mol. Biol., 15:939-947, 2008), sulfur oxygenase reductase (SOR) nanoparticles (e.g., Urich et al., Science, 311:996-1000, 2006, incorporated herein by reference) see), lumagine synthase nanoparticles (see, e.g., Zhang et al., J. Mol. Biol., 306: 1099-1114, 2001), or pyruvate dehydrogenase nanoparticles (see, e.g., herein) Izard et al., PNAS 96: 1240-1245, 1999). Ferritin, encapsulin, SOR, lumagine synthase, and pyruvate dehydrogenase are monomeric proteins that self-assemble into globular protein complexes consisting, in some cases, of 24, 60, 24, 60, and 60 protein subunits, respectively. Ferritin, encapsulin, SOR, lumagine synthase and pyruvate dehydrogenase monomers are linked to a peptide according to the invention or a protein according to the invention and self-assemble into protein nanoparticles displaying antigens/epitopes disclosed on the surface. , which can be administered to a subject to stimulate an immune response against the peptide according to the invention or the protein according to the invention.

Protein nanoparticle particles comprising an immunogen according to the invention as described herein are in particular protein nanoparticles comprising a peptide according to the invention or a protein according to the invention. Preferred embodiments of protein nanoparticles comprising the peptide according to the invention or the protein according to the invention correspond to preferred embodiments of the peptide according to the invention or the protein according to the invention.

For example, a protein nanoparticle may comprise one or more of any of the disclosed peptides, which protein nanoparticle preferably binds specifically to an antibody according to the invention described herein.

Non-limiting examples of nanoparticles include ferritin nanoparticles, encapsulin nanoparticles, and sulfur oxygenase reductase (SOR) nanoparticles, which are monomeric subunits comprising ferritin protein, encapsulin protein, and SOR protein, respectively. It consists of an assembly of units. For constructing protein nanoparticles comprising a peptide according to the invention or a protein according to the invention, the peptide according to the invention or the protein according to the invention is generally (such as a ferritin protein, an encapsulin protein or a SOR protein) Linked to subunits of protein nanoparticles. The fusion protein self-assembles into nanoparticles under appropriate conditions.

Preferably, the protein nanoparticles are thus ferritin nanoparticles, encapsulin nanoparticles, sulfur oxygenase reductase (SOR) nanoparticles, lumagine synthase nanoparticles or pyruvate dehydrogenase nanoparticles. More preferably, the protein nanoparticles are ferritin nanoparticles.

Ferritin nanoparticles and their use for immunization purposes (e.g., against influenza antigens) are known in the art (e.g., Kanekiyo et al., incorporated herein by reference in their entirety). al., Nature, 499: 102-106, 2013). Accordingly, preferred protein nanoparticles are ferritin nanoparticles. For example, any of the disclosed immunogens (in particular a peptide according to the invention or a protein according to the invention) may be linked to a ferritin polypeptide or a hybrid of different ferritin polypeptides that make up a ferritin protein nanoparticle. Therefore, protein nanoparticles containing the peptide according to the invention or the protein according to the invention are preferably ferritin nanoparticles.

Ferritin is a globular protein found in all animals, bacteria, and plants that controls the rate and location of polynuclear Fe(III)203 formation primarily through the transport of hydrated iron ions and protons to the mineralized core. It plays a role. The globular form of ferritin is composed of monomeric subunits, which are polypeptides with a molecular weight of approximately 17-20 kDa. An example of the sequence of one such monomeric subunit is shown as SEQ ID NO: 331:

Ferritin polypeptide:

MLKDIIKLLNEQVNKEMNSSNLYMSMSSWCYTHSLDGAGLFLFDHAAEEYEHAKKLIVFLNENNNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKGKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS

(SEQ ID NO: 331)

The globular form of ferritin contains 24 monomeric, subunit proteins and has a capsid-like structure with 432 symmetries. Methods of constructing ferritin nanoparticles are known to those skilled in the art and are further described herein (e.g., Zhang, Int. J, incorporated herein by reference in its entirety) Mol. Sci., 12:5406-5421, 2011).

For example, the ferritin polypeptide may be E. coli ferritin, Helicobacter pylori ferritin, human light chain ferritin, bullfrog ferritin or E. coli-human hybrid ferritin, E. coli-bullfrog hybrid ferritin, or human- It may be a hybrid thereof, such as bullfrog hybrid ferritin. Amino acid sequences of exemplary ferritin polypeptides to be combined with peptides according to the invention or proteins according to the invention and nucleic acid sequences encoding ferritin polypeptides can be found in GENBANK®, e.g., available in its entirety on April 19, 2017, herein. ZP 03085328, ZP 06990637, EJB64322, specifically incorporated by reference. l, AAA35832, NP 000137 can be found in AAA49532, AAA49525, AAA49524 and AAA49523. Preferably, the peptide according to the invention or the protein according to the invention has an amino acid sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 97%) identical to the amino acid sequence set forth in SEQ ID NO:331. It is linked to the ferritin protein containing.

Preferably, the ferritin polypeptide is Helicobacter pylori ferritin (such as the ferritin polypeptide set forth in SEQ ID NO:331). More preferably, the ferritin polypeptide comprises a substitution of a cysteine residue at position 31, such as a C31S, C31A or C31V substitution. The peptide according to the invention or the protein according to the invention preferably further comprises a substitution of a cysteine residue at position 31 of the ferritin polypeptide (such as the ferritin polypeptide set forth in SEQ ID NO: 331), such as a C31S, C31A or C31V substitution. May be linked to Helicobacter pylori ferritin.

Preferably, the peptide according to the invention or the protein according to the invention may be linked to an encapsulin polypeptide to constitute an encapsulin nanoparticle. Therefore, protein nanoparticles containing the peptide according to the invention or the protein according to the invention are preferably encapsulin nanoparticles. Encapsulin proteins are a family of conserved bacterial proteins, also known as linocin-like proteins, that form large protein assemblies that function as minimal compartments for packaging enzymes. The encapsulin assembly is composed of monomeric subunits, which are polypeptides with a molecular weight of approximately 30 kDa. An example of the sequence of one such monomeric subunit is provided as SEQ ID NO: 332:

Encapsulin polypeptide:

MEFLKRSFAPLTEKQWQEIDNRAREIFKTQLYGRKFVDVEGPYGWEYAAHPLGEVEVLSDENEVVKWGLRKSPLPLIELRATFTLDLWELDNLERGKPNVDLSSLEETVRKVAEFEDEVIFRGCEKSGVKGLLSFEERKIECGSTPKDLLEAIVRALSIFSKDGIEGPYTLVINTDRWINFLKEEAGHYPLEKRVEECLRGGKIITTPRIEDALV VSERGGDFKLILGQDLSIGYEDREKDAVRLFITETFTFQVVNPEALILLKF

(SEQ ID NO: 332)

After production, the monomeric subunits self-assemble into a globular encapsulin assembly containing 60 monomeric subunits. Methods of constructing encapsulin nanoparticles are known to those skilled in the art and are further described herein (e.g., Sutter et al., incorporated herein by reference in their entirety). al., Nature Struct. and Mol. Biol., 15:939-947, 2008). In a specific example, the encapsulin polypeptide is a bacterial encapsulin, such as an Escherichia coli or Thermotoga maritime encapsulin.

An exemplary encapsulin sequence to be combined with a peptide according to the invention or a protein according to the invention is set forth in SEQ ID NO: 332.

Preferably, a peptide according to the invention or a protein according to the invention may be linked to a SOR polypeptide to constitute a sulfur oxygenase reductase (SOR) nanoparticle. Therefore, protein nanoparticles comprising a peptide according to the invention or a protein according to the invention are preferably SOR nanoparticles. The SOR protein is a microbial protein (e.g. from the thermoacidophilic archaeon Acidianus ambivalen) that forms a 24 subunit protein assembly. Methods for constructing SOR nanoparticles are described herein. are known to those skilled in the art to which the invention pertains (see, for example, Urich et al., Science, 311:996-1000, 2006, which is incorporated herein by reference in its entirety).

Additionally, the peptide according to the invention or the protein according to the invention can also be linked to a lumagene synthase polypeptide to constitute a lumagene synthase nanoparticle. Therefore, the protein nanoparticles containing the peptide according to the present invention or the protein according to the present invention are preferably lumagine synthase nanoparticles.

Additionally, the peptide according to the invention or the protein according to the invention may be linked to a pyruvate dehydrogenase polypeptide to constitute pyruvate dehydrogenase. Therefore, it is preferable that the protein nanoparticles containing the peptide according to the present invention or the protein according to the present invention are pyruvate dehydrogenase nanoparticles.

Additional preferred examples of protein nanoparticles, and methods of obtaining them, are discussed in Warangkana Lohcharoenkal, Liying Wang, Yi Charlie Chen, and Yon Rojanasakul, “Protein Nanoparticles as Drug Delivery Carriers for Cancer Therapy,” BioMed Research International, incorporated herein by reference. , vol. 2014, Article ID 180549, 12 pages, 2014. Doi:10.1155/2014/180549.

Preferably, the peptide according to the invention or the protein according to the invention is linked together with a linker such as a GS-linker known in the art, for example ferritin, encapsulin, SOR, lumagin synthase or pyruvic acid. It is linked to the N- or C-terminus of a nanoparticle protein, such as a dehydrogenase protein. The construct is preferably prepared in HEK 293 cells, especially since the fusion protein can be secreted from these cells and self-assemble into nanoparticles. Nanoparticles can be purified by several different chromatographic procedures, such as known techniques, for example Mono Q (anion exchange) followed by size exclusion (SUPEROSE® 6) chromatography.

The invention also provides (i) a peptide according to the invention and (ii) a monomeric subunit of a nanoparticle protein such as ferritin, encapsulin, SOR, lumagin synthase or pyruvate dehydrogenase protein, or in a globular form of the protein. Provided are fusion proteins comprising portions thereof capable of inducing self-assembly of monomeric subunits. The amino acid sequence from the monomeric subunit of any known nanoparticle protein, such as ferritin, encapsulin, SOR, lumagine synthase or pyruvate dehydrogenase protein, can be used in particular to allow the monomeric subunit to carry the peptide according to the invention on its surface. As long as they can self-assemble into displaying nanoparticles, they can be used to produce fusion proteins with peptides according to the invention or proteins according to the invention.

The fusion protein need not contain the full-length sequence of a monomeric subunit polypeptide of a nanoparticle protein, such as ferritin, encapsulin, SOR, lumagine synthase or pyruvate dehydrogenase protein. A portion or region of a monomeric subunit polypeptide may be used as long as the portion contains an amino acid sequence that directs self-assembly of the monomeric subunit into the globular form of the protein.

In some embodiments, it may be useful to engineer mutations into the amino acid sequence of monomeric ferritin, encapsulin, SOR, lumagin synthase, or pyruvate dehydrogenase subunits. For example, it may be useful to alter sites such as enzyme recognition sites or glycosylation sites to provide advantageous properties (e.g., half-life) to the fusion protein.

A person skilled in the art to which the present invention pertains will know that the fusion of the peptide according to the present invention or the protein according to the present invention to ferritin, encapsulin, SOR, lumagin synthase or pyruvate dehydrogenase protein is the peptide according to the present invention or the present invention. The portion of the fusion protein comprising the protein according to the invention does not interfere with the self-assembly of the monomeric ferritin, encapsulin, SOR, lumagin synthase or pyruvate dehydrogenase subunit into a globular protein, and the ferritin of the fusion protein It will be appreciated that the encapsulin, SOR, lumagine synthase or pyruvate dehydrogenase protein portion should be carried out so as not to interfere with the ability of the peptide according to the invention or the protein according to the invention to elicit an immune response.

In general, the nanoparticle protein and the peptide according to the present invention or the protein according to the present invention can be directly combined without affecting the activity of either part. Alternatively, the nanoparticle protein and the peptide according to the invention or the protein according to the invention are linked using linker (also called spacer) sequences. For example, ferritin, encapsulin, SOR, lumagine synthase or pyruvate dehydrogenase protein and the peptide according to the invention or the protein according to the invention can be directly bound without affecting the activity of either part. . Alternatively, the ferritin, encapsulin, SOR, lumagine synthase or pyruvate dehydrogenase protein and the peptide according to the invention or the protein according to the invention are linked using a linker (also called spacer) sequence.

The linker sequences maintain the ability of the fusion protein to assemble into nanoparticles and are also linked to each other to induce an immune response against malaria parasites such as ferritin, encapsulation of the fusion protein comprising the peptide according to the invention or the protein according to the invention. It can be designed to position RIN, SOR, lumagine synthase or pyruvate dehydrogenase moieties and portions of the fusion protein.

Preferably, the linker sequence contains amino acids. Preferred amino acids for use are those with small side chains and/or are uncharged. These amino acids are unlikely to interfere with proper folding and activity of the fusion protein. Accordingly, the preferred amino acids for use in the linker sequence, alone or in combination, are serine, glycine, and alanine. One example of such a linker sequence is SGG. Amino acids can be added or subtracted as needed. A person skilled in the art to which the present invention pertains can determine an appropriate linker sequence for the construction of protein nanoparticles.

Preferably, the protein nanoparticles have a molecular weight of 100 to 5000 kDa, such as about 500 to 4600 kDa. More preferably, when the protein nanoparticles comprise a peptide according to the invention or a protein according to the invention, the ferritin nanoparticles have an approximate molecular weight of about 650 kDa and the encapsulin nanoparticles have an approximate molecular weight of about 2100 kDa. The SOR nanoparticles have an approximate molecular weight of about 1000 kDa, the lumagine synthase nanoparticles have an approximate molecular weight of about 4000 kDa, and the pyruvate dehydrogenase nanoparticles have an approximate molecular weight of about 4600 kDa. .

The peptide according to the invention or the protein according to the invention linked to ferritin, encapsulin, SOR, lumazine synthase or pyruvate dehydrogenase protein is ferritin nanoparticle, encapsulin nanoparticle, SOR nanoparticle, lumazine synthase, respectively. Nanoparticles can self-assemble into multi-subunit protein nanoparticles, typically referred to as pyruvate dehydrogenase nanoparticles. Nanoparticles containing the peptide according to the present invention or the protein according to the present invention are natural ferritin, encapsulin, SOR, lumagine synthase or pyruvate dehydrogenase nano particles that do not contain the peptide according to the present invention or the protein according to the present invention. It has substantially the same structural properties as the particle. That is, they contain 24, 60, 24, 60 or 60 subunits (respectively) and have similar corresponding symmetries.

Additionally, the peptide according to the invention, the protein according to the invention, the virus-like particle according to the invention, or the protein nanoparticle according to the invention preferably has a K _d of 1 μM or less. It is preferable to specifically bind to the antibody according to.

As used herein, “Kd” refers to the dissociation constant for a given interaction, such as a polypeptide-ligand interaction or antibody-antigen interaction. For example, in the case of a bimolecular interaction of an antibody (such as an antibody according to the invention as described below) and an antigen (such as a peptide according to the invention or a protein according to the invention), the individual components of the bimolecular interaction It is the concentration divided by the concentration of the complex. Methods for Determining the Kd of an Antibody: Antigen interactions are familiar to those skilled in the art.

Antibodies according to the invention

Binding of antibodies to peptides according to the invention

In a further aspect the invention provides an antibody, or antigen-binding fragment thereof, that (specifically) binds to a peptide according to the invention. That is, the antibody according to the present invention, or antigen-binding fragment thereof, can recognize the epitope corresponding to the peptide according to the present invention, especially the CSP epitope. Accordingly, the antibody according to the invention binds to the CSP epitope located at the junction between the N-terminus of CSP and the NANP-repeat region and close to the functionally important region I of CSP.

Antibodies that bind to the above epitopes, and therefore to the peptides according to the invention, have surprisingly been found to significantly reduce the liver parasite burden in vivo, suggesting that these antibodies are capable of (i) sporozoite invasion and (ii) liver stage parasite proliferation in vivo. This indicates that it can be strongly suppressed. Thereby, it is possible to prevent and/or treat disease in an individual, as well as suppress the spread of the disease in the population.

Preferably, the antibody, or antigen-binding fragment thereof according to the invention is a human antibody. The antibody or antigen-binding fragment thereof according to the present invention is preferably a monoclonal antibody, preferably a human monoclonal antibody. Additionally, it is preferable that the antibody or antigen-binding fragment thereof according to the present invention is a recombinant antibody.

Preferably, the antibody, or antigen-binding fragment thereof according to the invention comprises an Fc portion. More preferably, the Fc portion is of human origin, eg human IgG1, IgG2, IgG3 and/or IgG4, so human IgG1 is particularly preferred.

As used herein, the term "Fc portion" refers to the hinge region immediately upstream of the papain cleavage site (e.g., residue 216 in native IgG, the first residue of the heavy chain constant region is considered 114). refers to a sequence derived from a portion of an immunoglobulin heavy chain starting at and ending at the C-terminus of the immunoglobulin heavy chain. Accordingly, the Fc portion may be a complete Fc portion or a portion (e.g., domain) thereof. A complete Fc portion includes at least a hinge domain, a CH2 domain, and a CH3 domain (e.g., EU amino acid positions 216-446). An additional lysine residue (K) is sometimes present at the extreme C-terminus of the Fc portion, but is often cleaved from the mature antibody. Each amino acid position within the Fc portion is numbered according to the EU numbering system known in the art by Kabat, see, for example, Kabat et al., in "Sequences of Proteins of Immunological Interest", U.S. Dept. See Health and Human Services, 1983 and 1987.

Preferably, in the context of the present invention, the Fc portion comprises at least one of: a hinge (e.g., upper, middle and/or lower hinge region) domain, a CH2 domain, a CH3 domain, or a variant, portion, or fragment thereof. Includes. In a preferred embodiment, the Fc portion comprises at least a hinge domain, a CH2 domain, or a CH3 domain. More preferably, the Fc portion is a complete Fc portion. The Fc portion may also contain one or more amino acid insertions, deletions, or substitutions relative to naturally occurring Fc portions. For example, at least one of the hinge domain, CH2 domain, or CH3 domain (or part thereof) may be deleted. For example, the Fc portion may comprise (i) a hinge domain (or portion thereof) fused to a CH2 domain (or portion thereof), (ii) a hinge domain (or portion thereof) fused to a CH3 domain (or portion thereof), ( iii) a CH2 domain (or portion thereof) fused to a CH3 domain (or portion thereof), (iv) a hinge domain (or portion thereof), (v) a CH2 domain (or portion thereof), or (vi) a CH3 domain or portion thereof. It may include or consist of a part.

Those skilled in the art will recognize that the Fc portion can be modified in amino acid sequence to vary from the complete Fc portion of a naturally-occurring immunoglobulin molecule while retaining at least one desirable function conferred by the naturally-occurring Fc portion. You will understand that it exists. These functions include Fc receptor (FcR) binding, regulation of antibody half-life, ADCC function, protein A binding, protein G binding, and complement binding. Some of the naturally occurring Fc portions responsible and/or essential for these functions are well known to those skilled in the art.

For example, to activate the complement cascade, C1q binds to at least two molecules of IgG1 or one molecule of IgM attached to an antigenic target (Ward, ES, and Ghetie, V., Ther. Immunol 2 (1995 ) 77-94). Burton, DR described that the heavy chain region containing amino acid residues 318 to 337 is involved in complement fixation (Mol. Immunol. 22 (1985) 161-206). Using site-directed mutagenesis, Duncan, AR, and Winter, G. reported that Glu318, Lys320, and Lys322 form a binding site for C1q (Nature 332 (1988) 738-740). The role of residues Glu318, Lys320 and Lys 322 in binding of C1q was confirmed by the ability of a short synthetic peptide containing these residues to inhibit complement-mediated lysis.

For example, FcR binding may be mediated by the interaction of the Fc portion (of an antibody) with the Fc receptor (FcR), a specialized cell surface receptor on hematopoietic cells. Fc receptors belong to the immunoglobulin superfamily and are responsible for the elimination of antibody-coated pathogens by phagocytosis of immune complexes and lysis of red blood cells and various other cellular targets (e.g. tumor cells) coated with the corresponding antibodies. All have been shown to be mediated through antibody-dependent cell-mediated cytotoxicity (ADCC; Van de Winkel, JG, and Anderson, CL, J. Leukoc. Biol. 49 (1991) 511-524). FcRs are defined by their specificity for immunoglobulin classes; Fc receptors are referred to as FcγR for IgG antibodies, FcεR for IgE, FcαR for IgA, etc., and neonatal Fc receptors are referred to as FcRn. Fc receptor binding has been described for example by Ravetch, JV, and Kinet, JP, Annu. Rev. Immunol. 9 (1991) 457-492; Capel, PJ, et al., Immunomethods 4 (1994) 25-34; de Haas, M., et al., J Lab. Clin. Med. 126 (1995) 330-341; and Gessner, J.E., et al., Ann. Hematol. 76 (1998) 231-248.

Cross-linking of receptors by the Fc domain of natural IgG antibodies (FcγR) produces a wide range of effectors, including phagocytosis, antibody-dependent cellular cytotoxicity, and release of inflammatory mediators, as well as clearance of immune complexes and regulation of antibody production. causes function. Therefore, an Fc portion that provides cross-linking of the receptor (FcγR) is preferred. In humans, three classes of FcγRs have been characterized, which are: (i) FcγRI (CD64), which binds monomeric IgG with high affinity and is expressed on macrophages, monocytes, neutrophils and eosinophils; (ii) binds complexed IgG with medium to low affinity, is widely expressed, especially on leukocytes, is known to play a central role in antibody-mediated immunity, and performs different functions in the immune system but has a low affinity similar to that of IgG-Fc; FcγRII (CD32), which binds with high affinity and whose ectodomains can be divided into the highly homologous FcγRIIA, FcγRIIB and FcγRIIC; and (iii) FcγRIII (CD16), which binds IgG with medium to low affinity and exists in two types: FcγRIIIA, which is found on NK cells, macrophages, eosinophils and some monocytes and T cells, and ADCC, which is highly expressed on neutrophils. Mediates FcγRIIIB. FcγRIIA is found on many cells involved in apoptosis (e.g. macrophages, monocytes, neutrophils) and appears to be able to activate the apoptotic process. FcγRIIB appears to play a role in the inhibitory process and is found on B-cells, macrophages and mast cells, and eosinophils. Importantly, 75% of all FcγRIIB is found in the liver (Ganesan, L. P. et al., 2012: FcγRIIb on liver sinusoidal endothelium clears small immune complexes. Journal of Immunology 189: 4981-4988), and FcγRIIB is located in the liver, called LSEC. It is abundantly expressed in the liver sinusoidal endothelium and intrahepatic Kupffer cells, and LSEC is a major site of small immune complex clearance (Ganesan, L. P. et al., 2012: FcγRIIb on liver sinusoidal endothelium clears small immune complexes. Journal of Immunology 189: 4981-4988).

Therefore, in the present invention, such antibodies capable of binding to FcγRIIb, and antigen-binding fragments thereof, such as antibodies comprising an Fc portion, especially an Fc region, for binding to FcγRIIb, such as IgG-type antibodies, are preferred. Additionally, Chu, S. Y. et al., 2008: Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcγRIIb with Fc-engineered antibodies. It is possible to engineer the Fc portion to improve FcγRIIB binding by introducing mutations S267E and L328F as described in Molecular Immunology 45, 3926-3933. Thereby, the clearance of immune complexes can be improved (Chu, S., et al., 2014: Accelerated Clearance of IgE In Chimpanzees Is Mediated By Xmab7195, An Fc-Engineered Antibody With Enhanced Affinity For Inhibitory Receptor FcγRIIb . Am J Respir Crit, American Thoracic Society International Conference Abstracts). Accordingly, in the context of the present invention, such antibodies, or antigen-binding fragments thereof, are specifically described in Chu, S. Y. et al., 2008: Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcγRIIb with Fc-engineered antibodies. . It is preferred to include an engineered Fc portion with mutations S267E and L328F as described by Molecular Immunology 45, 3926-3933.

In B-cells, it appears to function to inhibit isotype switching and the production of additional immunoglobulins, for example of the IgE class. In macrophages, FcγRIIB acts to inhibit phagocytosis mediated through FcγRIIA. In eosinophils and mast cells, the b form may help inhibit activation of these cells through IgE binding to individual receptors.

With respect to FcγRI binding, modifications to native IgG in at least one of E233-G236, P238, D265, N297, A327 and P329 reduce binding to FcγRI. IgG2 residues at positions 233-236 substituted for IgG1 and IgG4 reduced binding to FcγRI 103-fold and eliminated human monocyte responses to antibody-sensitive erythrocytes (Armour, K. L., et al. Eur. J. Immunol. 29 (1999) 2613-2624). Regarding FcγRII binding, reduced binding to FcγRIIA is found for example for at least one of the following IgG mutations: E233-G236, P238, D265, N297, A327, P329, D270, Q295, A327, R292 and K414. With regard to FcγRIII binding, reduced binding to FcγRIIIA is e.g. E233-G236, P238, D265, N297, A327, P329, D270, Q295, A327, S239, E269, E293, Y296, V303, A327, K338 and D376. At least one mutation is found. Mapping of binding sites on human IgG1 to Fc receptors, the above-mentioned mutation sites, and methods for measuring binding to FcγRI and FcγRIIA are described in Shields, R. L., et al., J. Biol. Chem. 276 (2001) 6591-6604.

With regard to binding to FcγRII, two regions of native IgG Fc are involved in the interaction of FcγRII and IgG, namely (i) the lower hinge region of IgG Fc, especially amino acid residues L, L, G, G ((234 - 237 , EU numbering), and (ii) adjacent regions of the CH2 domain of IgG Fc, particularly the loops and strands of the upper CH2 domain adjacent to the lower hinge region, for example the region of P331 (Wines , B.D., et al., J. Immunol. 2000; 164: 5313 - 5318). Additionally, FcγRI appears to bind to the same site on IgG Fc, whereas FcRn and Protein A appear to be at the CH2-CH3 boundary. Binds to different sites on the body (Wines, B.D., et al., J. Immunol. 2000; 164: 5313 - 5318)

For example, the Fc portion may comprise or consist of at least a portion of the Fc portions known in the art to be required for FcRn binding or extended half-life. Alternatively or additionally, the Fc portion of the antibody of the invention comprises at least a portion known in the art to be required for protein A binding and/or the Fc portion of the antibody of the invention is required for protein G binding. It includes at least a portion of Fc molecules known in the art to which the present invention pertains. Preferred Fc portions include at least some of those known in the art to be required for FcγR binding. As noted above, a preferred Fc portion comprises at least (i) the lower hinge region of a native IgG Fc, especially amino acid residues L, L, G, G (234 - 237, EU numbering) and (ii) the CH2 domain of a native IgG Fc. Proximal regions, especially the loops and chains of the upper CH2 domain adjacent to the lower hinge region, e.g. the P331 region, e.g. between amino acids 320 to 340 (EU numbering) of the native IgG Fc, e.g. around P331 may comprise a region of at least 3, 4, 5, 6, 7, 8, 9 or 10 consecutive amino acids in the upper CH2 domain.

Preferably, the antibody, or antigen-binding fragment thereof according to the invention comprises an Fc region. As used herein, the term “Fc region” refers to the portion of an immunoglobulin formed by two or more Fc portions of an antibody heavy chain. For example, the Fc region may be a monomeric or “single-chain” Fc region (i.e., scFc region). A single chain Fc region consists of an Fc portion linked within a single polypeptide chain (e.g., encoded by a single contiguous nucleic acid sequence). An exemplary scFc region is disclosed in WO 2008/143954 A2. Preferably, the Fc region is a dimeric Fc region. “Dimeric Fc region” or “dcFc” refers to a dimer formed by the Fc portions of two distinct immunoglobulin heavy chains. A dimeric Fc region may be a homodimer of two identical Fc portions (e.g., the Fc region of a naturally occurring immunoglobulin) or a heterodimer of two non-identical Fc portions.

The Fc portion of the Fc region may be of the same or different class and/or subclass. For example, the Fc portion can be derived from an immunoglobulin of the IgG1, IgG2, IgG3, or IgG4 subclass (e.g., human immunoglobulin). Preferably, the Fc portion of the Fc region is of the same class and subclass. However, the Fc region (or one or more Fc portions of an Fc region) may also be chimeric, and a chimeric Fc region may comprise Fc portions derived from different immunoglobulin classes and/or subclasses. For example, at least two Fc portions of a dimeric or single-chain Fc region may be from different immunoglobulin classes and/or subclasses. Additionally or alternatively, the chimeric Fc region may comprise one or more chimeric Fc portions. For example, a chimeric Fc region or portion may comprise one or more portions derived from an immunoglobulin of the first subclass (e.g., IgG1, IgG2, or IgG3 subclass), while the Fc region or portion The rest are different subclasses. For example, the Fc region or portion of an Fc polypeptide may comprise CH2 and/or CH3 domains derived from an immunoglobulin of a first subclass (e.g., an IgG1, IgG2, or IgG4 subclass) and a CH2 and/or CH3 domain derived from an immunoglobulin of a second subclass (e.g., , may contain a hinge region from an immunoglobulin of the IgG3 subclass). For example, the Fc region or portion may have a hinge and/or CH2 domain derived from an immunoglobulin of a first subclass (e.g., an IgG4 subclass) and an immunoglobulin of a second subclass (e.g., an IgG1, IgG2, or IgG3 subclass). class) of immunoglobulins. For example, a chimeric Fc region can be an Fc portion (e.g., a complete Fc portion) from an immunoglobulin for a first subclass (e.g., an IgG4 subclass) and an Fc portion (e.g., a complete Fc portion) from an immunoglobulin for a first subclass (e.g., an IgG1, and an Fc portion from an immunoglobulin of the IgG2 or IgG3 subclass. For example, the Fc region or portion may comprise the CH2 domain of an IgG4 immunoglobulin and the CH3 domain of an IgG1 immunoglobulin. For example, the Fc region or portion may comprise a CH1 domain and a CH2 domain from an IgG4 molecule and a CH3 domain from an IgG1 molecule. For example, the Fc region or portion may comprise a portion of the CH2 domain from a particular subclass of antibody, e.g., EU positions 292-340 of the CH2 domain. For example, the Fc region or portion may include positions 292-340 of CH2 derived from the IgG4 portion and the remaining amino acids of CH2 derived from the IgG1 portion (alternatively, 292-340 of CH2 may comprise positions 292-340 of CH2 from the IgG1 portion and IgG4 may be derived from the remainder of CH2 derived from the portion).

Additionally, the Fc region or portion may (additionally or alternatively) comprise, for example, a chimeric hinge region. For example, a chimeric hinge may be derived, for example, in part from an IgG1, IgG2 or IgG4 molecule (e.g., upper and lower middle hinge sequences) and in part from an IgG3 molecule (e.g., middle hinge sequence). In another example, the Fc region or portion may include a chimeric hinge derived partly from an IgG1 molecule and partly from an IgG4 molecule. In another example, the chimeric hinge may include upper and lower hinge domains from an IgG4 molecule and a middle hinge domain from an IgG1 molecule. This chimeric hinge can be achieved, for example, by introducing a proline substitution (Ser228Pro) at EU position 228 in the middle hinge domain of the IgG4 hinge region. In another embodiment, the chimeric hinge, which may include amino acids at EU positions 233-236, is derived from an IgG2 antibody and/or the Ser228Pro mutation, and the remaining amino acids of the hinge are derived from an IgG4 antibody (e.g., of the sequence ESKYGPPCPPCPAPPVAGP chimeric hinge). Additional chimeric hinges that can be used in the Fc part of the antibodies according to the invention are described in US 2005/0163783 A1.

In the present invention, the Fc portion or Fc region preferably comprises or consists of an amino acid sequence derived from a human immunoglobulin sequence (e.g., the Fc region or Fc portion from a human IgG molecule). However, the polypeptide may contain one or more amino acids from other mammalian species. For example, a primate Fc portion or primate binding site may be included in the polypeptides of the invention. Alternatively, one or more murine amino acids may be present in the Fc portion or Fc region.

Preferably, the antibody according to the invention, in particular in addition to the Fc part as described above, is derived from a constant region, in particular from an IgG constant region, preferably from the constant region of IgG1, more preferably from the constant region of human IgG1. Includes other parts. More preferably, the antibody according to the invention comprises, in particular, in addition to the Fc part as described above, all other parts of the constant region, especially all other parts of the constant region of an IgG, preferably all other parts of the constant region of an IgG1, More preferably it includes all other parts of the constant region of human IgG1.

A particularly preferred sequence of the constant region is the amino acid sequence according to SEQ ID NOs: 313-315 (nucleic acid sequence according to SEQ ID NOs: 316 - 318). Preferably, the amino acid sequence of the IgG1 CH1-CH2-CH3 is according to SEQ ID NO:313 or a functional sequence variant thereof described herein.

As mentioned above, particularly preferred antibodies according to the invention comprise an (intact) Fc region derived from human IgG1. More preferably, the antibody according to the invention comprises, in particular, in addition to the (complete) Fc region derived from a human IgG1, all other parts of the constant region of an IgG, preferably all other parts of the constant region of an IgG1, more preferably human Contains all other parts of the constant region of IgG1.

Preferably, the antibody according to the invention comprises an (complete) Fc part/Fc region and its interaction/binding with the FcR is intact. Typically, binding of antibodies to the Fc receptor is assessed by ELISA (Hessell AJ, Hangartner L, Hunter M, Havenith CEG, Beurskens FJ, Bakker JM, Lanigan CMS, Landucci G, Forthal DN, Parren PWHI, et al.: Fc receptor but not complement binding is important in antibody protection against HIV. Nature 2007, 449:101-104; Grevys A, Bern M, Foss S, Bratlie DB, Moen A, Gunnarsen KS, Aase A, Michaelsen TE, Sandlie I, Andersen JT: Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions. 2015, 194:5497-5508) or flow-cytometry (Perez LG, Costa MR, Todd CA, Haynes BF, Montefiori DC: Utilization of immunoglobulin G Fc receptors by human immunodeficiency virus type 1: a specific role for antibodies against the membrane-proximal external region of gp41. J Virol 2009, 83:7397-7410; Piccoli L, Campo I, Fregni CS, Rodriguez BMF, Minola A, Sallusto F, Luisetti M, Corti D, Lanzavecchia A: Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. Nat Commun 2015, 6:1-9) It can be measured by various methods known to those skilled in the art.

In general, antibodies according to the invention may be glycosylated. For example, N-linked glycans attached to the CH2 domain of the heavy chain can affect C1q and FcR binding to glycosylated antibodies with low affinity for these receptors. Accordingly, the CH2 domain of the Fc portion of the antibody according to the invention may contain one or more mutations, wherein a glycosylated residue is replaced by a non-glycosylated residue. Glycan structure can also affect activity, which can show differences in complement-mediated cell death, for example, depending on the number of galactose sugars (0, 1, or 2) at the biantennary chain end of the glycan. there is. Preferably, the glycans of the antibody do not elicit an immunogenic response in humans after administration.

Additionally, antibodies according to the invention may be modified by introducing random amino acid mutations into specific regions of the CH2 or CH3 domain of the heavy chain to alter their binding affinity to FcRs and/or their serum half-life compared to unmodified antibodies. It can be. Examples of such modifications include, but are not limited to, substitution of at least one amino acid from the heavy chain constant region selected from the group consisting of amino acid residues 250, 314, and 428.

Preferably, the antibody, or antigen-binding fragment thereof, according to the present invention comprises a variable region of the heavy chain (VH) of the antibody, or antigen-binding fragment thereof, which is a gene of the VH3 gene family ( (part), preferably encoding a nucleic acid comprising the VH3-30 gene (part).

In general, an antibody, or antigen-binding fragment thereof, according to the invention preferably comprises (at least) three complementarity determining regions (CDRs) on the heavy chain and (at least) three CDRs on the light chain. Generally, complementarity determining regions (CDRs) are hypervariable regions present in the heavy and light chain variable domains. Typically, the CDRs of the heavy chain and the linked light chain of the antibody together form an antigen receptor. Typically, the three CDRs (CDR1, CDR2 and CDR3) are arranged non-contiguously in the variable domain. Because antigen receptors typically consist of two variable domains (from two different polypeptide chains, i.e. heavy and light chains), there are six CDRs for each antigen receptor (heavy chain: CDRH1, CDRH2, and CDRH3; light chain: CDRL1, CDRL2). , and CDRL3). A single antibody molecule usually has two antigen receptors and therefore contains 12 CDRs. The CDRs on the heavy and/or light chains may be separated by framework regions (FRs), which are less “variable” regions than the CDRs in the variable domains. For example, a chain (or each chain) may consist of four framework regions separated by three CDRs.

The sequences of the heavy and light chains of exemplary antibodies of the invention, comprising three different CDRs on the heavy chain and three different CDRs on the light chain, were determined. The positions of CDR amino acids are defined according to the IMGT numbering system (IMGT: http://www.imgt.org/; cf. Lefranc, M.-P. et al. (2009) Nucleic Acids Res. 37, D1006-D1012 ).

Preferably, the antibody, or antigen-binding fragment thereof according to the invention comprises a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. Comprising a light chain, said at least one CDR, preferably at least one heavy chain CDRH3, has an amino acid sequence according to any one of SEQ ID NOs: 66, 84, 138, 156, 208, 226, 260, 278 and 296, or Sequence identity of at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% It contains or consists of a functional sequence variant thereof having a.

More preferably, the antibody, or antigen-binding fragment thereof according to the invention comprises a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. Comprising a light chain comprising, said at least one CDR, preferably at least one heavy chain CDRH3, is an amino acid sequence according to any one of SEQ ID NOs: 66, 84, 138, 208, 226 and 278, or at least 70%, at least A functional sequence thereof having a sequence identity of 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% Contains or consists of variants. Even more preferably, the antibody, or antigen-binding fragment thereof according to the invention comprises a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. Comprising a light chain comprising, said at least one CDR, preferably at least one heavy chain CDRH3, is an amino acid sequence according to SEQ ID NO:66 or according to SEQ ID NO:226, or at least 70%, at least 75%, at least 80% , comprising or consisting of a functional sequence variant thereof having a sequence identity of at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. do. Even more preferably, the antibody, or antigen-binding fragment thereof, according to the present invention has a heavy chain comprising at least one CDRH1, at least one CDRH2, and at least one CDRH3, and at least one CDRL1, at least one CDRL2, and at least one CDRL3. Comprising a light chain comprising, wherein at least one CDR, preferably at least one heavy chain CDRH3, has an amino acid sequence according to SEQ ID NO: 208 or according to SEQ ID NO: 278, or at least 70%, at least 75%, at least 80% %, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. It is composed. Most preferably, the antibody, or antigen-binding fragment thereof according to the invention comprises a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. Comprising a light chain comprising, said at least one CDR, preferably at least one heavy chain CDRH3, is an amino acid sequence according to SEQ ID NO: 84 or according to SEQ ID NO: 138, or at least 70%, at least 75%, at least 80% , comprising or consisting of a functional sequence variant thereof having a sequence identity of at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. do.

Preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain comprising the

(i) at least one heavy chain CDRH1 has the amino acid sequence according to SEQ ID NOs: 64, 82, 136, 154, 206, 224, 258, 276, and 294, or at least 70%, at least 75%, at least 80%, at least 85 %, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity;

(ii) at least one CDRH2 has an amino acid sequence according to SEQ ID NOs: 65, 83, 137, 155, 207, 225, 259, 277, and 295, or at least 70%, at least 75%, at least 80%, at least 85% , comprising functional sequence variants thereof having a sequence identity of at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one heavy chain CDRH3 has an amino acid sequence according to SEQ ID NOs: 66, 84, 138, 156, 208, 226, 260, 278 and 296, or at least 70%, at least 75%, at least 80%, at least 85% , including functional sequence variants thereof having a sequence identity of at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

More preferably, the antibody, or antigen-binding fragment thereof according to the invention has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one heavy chain CDRH1 has an amino acid sequence according to SEQ ID NOs: 64, 82, 136, 206, 224, and 276, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, a functional sequence variant thereof having a sequence identity of at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRH2 has an amino acid sequence according to SEQ ID NOs: 65, 83, 137, 207, 225, and 277, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least A functional sequence variant thereof having a sequence identity of 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%; and/or

(iii) at least one heavy chain CDRH3 has an amino acid sequence according to SEQ ID NOs: 66, 84, 138, 208, 226, and 278, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, and functional sequence variants thereof having a sequence identity of at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

Even more preferably, the antibody, or antigen-binding fragment thereof according to the invention has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one heavy chain CDRH1 has the amino acid sequence according to SEQ ID NO:64 or according to SEQ ID NO:224; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90% , comprising functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRH2 has an amino acid sequence according to SEQ ID NO:65 or according to SEQ ID NO:225, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, and functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one heavy chain CDRH3 has an amino acid sequence according to SEQ ID NO:66 or according to SEQ ID NO:226, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90% , including functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

Even more preferably, the antibody according to the present invention, or an antigen-binding fragment thereof, has a heavy chain comprising at least one CDRH1, at least one CDRH2, and at least one CDRH3, and at least one CDRL1, at least one CDRL2, and at least one heavy chain. Comprising a light chain comprising CDRL3, wherein

(i) at least one heavy chain CDRH1 has the amino acid sequence according to SEQ ID NO: 206 or according to SEQ ID NO: 276; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90% , comprising functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRH2 has an amino acid sequence according to SEQ ID NO: 207 or according to SEQ ID NO: 277, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, and functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one heavy chain CDRH3 has the amino acid sequence according to SEQ ID NO: 208 or according to SEQ ID NO: 278, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90% , including functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

Most preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one heavy chain CDRH1 has the amino acid sequence according to SEQ ID NO: 82 or according to SEQ ID NO: 136, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, and functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRH2 has an amino acid sequence according to SEQ ID NO: 83 or according to SEQ ID NO: 137, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, and functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one heavy chain CDRH3 has an amino acid sequence according to SEQ ID NO: 84 or according to SEQ ID NO: 138, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90% , including functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

The antibody, or antigen-binding fragment thereof, according to the invention has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and a light chain comprising at least one CDRL1, at least one CDRL2 and at least one CDRL3. It is also desirable to include the above

(i) at least one CDRL1 has an amino acid sequence according to SEQ ID NOs: 67, 85, 139, 157, 209, 227, 261, 279, and 297, or at least 70%, at least 75%, at least 80%, at least 85% , comprising functional sequence variants thereof having a sequence identity of at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRL2 has the amino acid sequence according to SEQ ID NOs: 68, 69, 86, 87, 140, 141, 158, 159, 210, 211, 228, 229, 262, 263, 280, 281, 298 and 299. , or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of Includes functional sequence variants thereof having sequence identity; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NOs: 70, 88, 142, 160, 212, 230, 264, 282, and 300, or at least 70%, at least 75%, at least 80%, at least 85% , including functional sequence variants thereof having a sequence identity of at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

More preferably, the antibody, or antigen-binding fragment thereof according to the invention has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one CDRL1 has an amino acid sequence according to SEQ ID NOs: 67, 85, 139, 209, 227, and 279; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, a functional sequence variant thereof having a sequence identity of at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRL2 has an amino acid sequence according to SEQ ID NOs: 68, 69, 86, 87, 140, 141, 210, 211, 228, 229, 280, and 281, or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NOs: 70, 88, 142, 212, 230, and 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, and functional sequence variants thereof having a sequence identity of at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

Even more preferably, the antibody, or antigen-binding fragment thereof according to the invention has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one CDRL1 has the amino acid sequence according to SEQ ID NO:67, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , comprising functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRL2 has an amino acid sequence according to SEQ ID NO: 68 or 69, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least A functional sequence variant thereof having a sequence identity of 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NO:70, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , including functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%.

Even more preferably, the antibody according to the present invention, or an antigen-binding fragment thereof, has a heavy chain comprising at least one CDRH1, at least one CDRH2, and at least one CDRH3, and at least one CDRL1, at least one CDRL2, and at least one heavy chain. Comprising a light chain comprising CDRL3, wherein

(i) at least one CDRL1 has an amino acid sequence according to SEQ ID NO: 209; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , comprising functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRL2 has an amino acid sequence according to SEQ ID NO: 210 or 211; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least A functional sequence variant thereof having a sequence identity of 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NO: 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , including functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%.

Even more preferably, the antibody, or antigen-binding fragment thereof according to the invention has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one CDRL1 has an amino acid sequence according to SEQ ID NO: 227; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , comprising functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRL2 has an amino acid sequence according to SEQ ID NO: 228 or 229; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least A functional sequence variant thereof having a sequence identity of 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NO:230, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , including functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%.

Even more preferably, the antibody according to the present invention, or an antigen-binding fragment thereof, has a heavy chain comprising at least one CDRH1, at least one CDRH2, and at least one CDRH3, and at least one CDRL1, at least one CDRL2, and at least one heavy chain. Comprising a light chain comprising CDRL3, wherein

(i) at least one CDRL1 has the amino acid sequence according to SEQ ID NO:279; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , comprising functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRL2 has an amino acid sequence according to SEQ ID NO: 280 or 281, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least A functional sequence variant thereof having a sequence identity of 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NO: 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , including functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%.

Particularly preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one CDRL1 has an amino acid sequence according to SEQ ID NO: 139; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , comprising functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRL2 has an amino acid sequence according to SEQ ID NO: 140 or 141; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least A functional sequence variant thereof having a sequence identity of 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NO: 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , including functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%.

Most preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDRL1, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one CDRL1 has an amino acid sequence according to SEQ ID NO:85; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , comprising functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%;

(ii) at least one CDRL2 has an amino acid sequence according to SEQ ID NO: 86 or 87, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least A functional sequence variant thereof having a sequence identity of 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NO:88, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , including functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98%, or at least 99%.

Preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 64-66; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (ii) SEQ ID NO: 82 - 84; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (iii) SEQ ID NO: 136 - 138; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (iv) SEQ ID NO: 154 - 156; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (v) SEQ ID NO: 206 - 208; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (vi) SEQ ID NO: 224 - 226; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (vii) SEQ ID NO: 258 - 260; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (viii) SEQ ID NO: 276 - 278; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (ix) SEQ ID NO: 294 - 296; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes CDRH1, CDRH2, and CDRH3 amino acid sequences along with their functional sequence variants having identity.

Antibodies according to the invention, or antigen-binding fragments thereof, comprise the CDRH1, CDRH2, and CDRH3 amino acid sequences and (i) SEQ ID NOs: 64 - 68 and 70; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (ii) SEQ ID NOs: 64 - 67 and 69 - 70; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (iii) SEQ ID NOs: 82 - 86 and 88; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (iv) SEQ ID NOs: 82 - 85 and 87 - 88; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (v) SEQ ID NOs: 136 - 140 and 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (vi) SEQ ID NOs: 136 - 139 and 141 - 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (vii) SEQ ID NOs: 154 - 158 and 160; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (viii) SEQ ID NOs: 154 - 157 and 159 - 160; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (ix) SEQ ID NOs: 206 - 210 and 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (x) SEQ ID NOs: 206 - 209 and 211 - 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xi) SEQ ID NOs: 224 - 228 and 230; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xii) SEQ ID NOs: 224 - 227 and 229 - 230; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xiii) SEQ ID NOs: 258 - 262 and 264; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xiv) SEQ ID NOs: 258 - 261 and 263 - 264; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xv) SEQ ID NOs: 276 - 280 and 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xvi) SEQ ID NOs: 276 - 279 and 281 - 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xvii) SEQ ID NOs: 294 - 298 and 300; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xviii) SEQ ID NOs: 294 - 297 and 299 - 300; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. It is preferred to include the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

More preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 64 - 68 and 70, respectively; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 64 - 67 and 69 - 70; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

More preferably, the antibody, or antigen-binding fragment thereof according to the invention has (i) SEQ ID NOs: 224 - 228 and 230; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 224 - 227 and 229 - 230; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Even more preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 276 - 280 and 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 276 - 279 and 281 - 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Even more preferably, the antibody, or antigen-binding fragment thereof, according to the present invention has (i) SEQ ID NOs: 206 - 210 and 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 206 - 209 and 211 - 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Particularly preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 136 - 140 and 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 136 - 139 and 141 - 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Most preferably, the antibody according to the invention, or antigen-binding fragment thereof, comprises (i) SEQ ID NOs: 82 - 86 and 88; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 82 - 85 and 87 - 88; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Moreover, the antibody, or antigen-binding fragment thereof according to the invention also comprises a heavy chain variable region (VH) and optionally a light chain variable region (VL), wherein the heavy chain variable region (VH) is SEQ ID NO: 71, 89, 143 , 161, 213, 231, 265, 283, and 301; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95 %, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.

Moreover, the antibody, or antigen-binding fragment thereof according to the invention (i) has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 71 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 72. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or Includes functional sequence variants thereof with at least 99% sequence identity; (ii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 89 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 90 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; (iii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 143 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, A functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 144 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; (iv) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 161 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, A functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 162 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; or (v) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 213 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 214 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; (vi) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 231 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, A functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 232 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; (vii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 265 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 266 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; (viii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 283 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, A functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 284 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; or (ix) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 301 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 302 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. It is desirable to include it.

More preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 71 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 72. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

More preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 231 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 232. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

Even more preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 283 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%. %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 284. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

Even more preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 213, or at least 70%, at least 75%, at least 80%, at least 85%, at least A functional sequence variant thereof having a sequence identity of 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable according to SEQ ID NO: 214 region (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or a functional sequence variant thereof with at least 99% sequence identity.

Particularly preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 143 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 144. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

Most preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 89 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 90. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

Preferably, the antibody or antigen-binding fragment thereof according to the invention is gMGG3, gMGG4, gMGH2, gMGH3, gMGU5, gMGU8, gMGU11, gMGU12 or gMGV3, and preferably, the antibody or antigen-binding fragment thereof is gMGG3, gMGG4. , gMGH2, gMGU5, gMGU8 or gMGU12, and more preferably the antibody or antigen-binding fragment thereof is gMGG4 or gMGH2.

The present inventors have isolated monoclonal antibodies (mAb) according to the invention, herein referred to as MGG3, MGG4, MGH2, MGH3, MGU5, MGU8, MGU11, MGU12 and MGV3 (see Tables 1 and 2, Example 1 ). Based on these antibodies, especially the VH and VL genes of these antibodies, the terms “gMGG3”, “gMGG4”, “gMGH2”, “gMGH3”, “gMGU5”, “gMGU8”, “gMGU11”, “ “gMGU12” and “gMGV3” refer to each “generic” antibody, or antigen-binding fragment thereof.

That is, “gMGG3” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 64, the CDRH2 amino acid sequence according to SEQ ID NO: 65, the CDRH3 amino acid sequence according to SEQ ID NO: 66, the CDRL1 amino acid sequence according to SEQ ID NO: 67, SEQ ID NO: 68 or an antibody having a CDRL2 amino acid sequence according to 69, and a CDRL3 amino acid sequence according to SEQ ID NO: 70, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 71 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 72.

“gMGG4” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 82, the CDRH2 amino acid sequence according to SEQ ID NO: 83, the CDRH3 amino acid sequence according to SEQ ID NO: 84, the CDRL1 amino acid sequence according to SEQ ID NO: 85, SEQ ID NO: 86 or 87 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 88, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 89 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 90.

“gMGH2” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 136, the CDRH2 amino acid sequence according to SEQ ID NO: 137, the CDRH3 amino acid sequence according to SEQ ID NO: 138, the CDRL1 amino acid sequence according to SEQ ID NO: 139, SEQ ID NO: 140 or 141 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 142, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 143 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 144.

“gMGH3” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 154, the CDRH2 amino acid sequence according to SEQ ID NO: 155, the CDRH3 amino acid sequence according to SEQ ID NO: 156, the CDRL1 amino acid sequence according to SEQ ID NO: 157, SEQ ID NO: 158 or 159 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 160, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 161 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 162.

“gMGU5” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 206, the CDRH2 amino acid sequence according to SEQ ID NO: 207, the CDRH3 amino acid sequence according to SEQ ID NO: 208, the CDRL1 amino acid sequence according to SEQ ID NO: 209, SEQ ID NO: 210 or 211 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 212, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 213 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 214.

“gMGU8” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 224, the CDRH2 amino acid sequence according to SEQ ID NO: 225, the CDRH3 amino acid sequence according to SEQ ID NO: 226, the CDRL1 amino acid sequence according to SEQ ID NO: 227, SEQ ID NO: 228 or 229 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 230, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 231 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 232.

“gMGU11” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 258, the CDRH2 amino acid sequence according to SEQ ID NO: 259, the CDRH3 amino acid sequence according to SEQ ID NO: 260, the CDRL1 amino acid sequence according to SEQ ID NO: 261, SEQ ID NO: 262 or 263 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 264, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 265 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 266.

“gMGU12” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 276, the CDRH2 amino acid sequence according to SEQ ID NO: 277, the CDRH3 amino acid sequence according to SEQ ID NO: 278, the CDRL1 amino acid sequence according to SEQ ID NO: 279, SEQ ID NO: 280 or 281 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 282, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 283 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 284.

“gMGV3” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 294, the CDRH2 amino acid sequence according to SEQ ID NO: 295, the CDRH3 amino acid sequence according to SEQ ID NO: 296, the CDRL1 amino acid sequence according to SEQ ID NO: 297, SEQ ID NO: 298 or 299 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 300, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 301 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 302.

Antibody binding to Plasmodium falciparum sporozoites

In a further aspect, the invention provides an antibody, or antigen-binding fragment thereof, that (specifically) binds to Plasmodium falciparum sporozoites. More preferably, the antibody according to the invention, or antigen-binding fragment thereof, binds (specifically) to a malaria parasite circosporozoite protein, most preferably to a malaria parasite circosporozoite protein according to SEQ ID NO: 24. . That is, the antibody or antigen-binding fragment thereof according to the present invention can recognize an epitope, especially the CSP epitope.

Preferably, the antibody, or antigen-binding fragment thereof according to the invention is a human antibody. The antibody or antigen-binding fragment thereof according to the present invention is preferably a monoclonal antibody, preferably a human monoclonal antibody. Additionally, it is preferable that the antibody or antigen-binding fragment thereof according to the present invention is a recombinant antibody.

Preferably, the antibody, or antigen-binding fragment thereof according to the invention comprises the Fc portion described above. It is understood that preferred embodiments of the Fc part of an antibody according to the invention, which binds to a peptide according to the invention, correspond to preferred embodiments of the Fc part of an antibody according to the invention, which binds to Plasmodium falciparum sporozoites. For example, the Fc portion is preferably of human origin, such as human IgG1, IgG2, IgG3 and/or IgG4, with human IgG1 being particularly preferred.

For all antibodies according to the invention, i.e. antibodies binding to peptides according to the invention and antibodies binding to Plasmodium falciparum sporozoites, it is also preferred that the antibody, or antigen-binding fragment thereof, does not comprise an Fc portion. In particular, the antibody or antigen-binding fragment thereof according to the present invention is preferably a purified antibody, single chain antibody, Fab, Fab', F(ab')2, Fv or scFv.

As described above, an antibody, or antigen-binding fragment thereof, according to the invention preferably comprises (at least) three complementarity determining regions (CDRs) on the heavy chain and (at least) three CDRs on the light chain. Generally, complementarity determining regions (CDRs) are hypervariable regions present in the heavy and light chain variable domains. Typically, the CDRs of the heavy chain and the linked light chain of the antibody together form an antigen receptor. Typically, the three CDRs (CDR1, CDR2 and CDR3) are arranged non-contiguously in the variable domain. Because antigen receptors typically consist of two variable domains (from two different polypeptide chains, i.e. heavy and light chains), each antigen receptor (heavy chain: CDRH1, CDRH2, and CDRH3; light chain: CDRL1, CDRL2, and CDRL3) There are 6 CDRs for A single antibody molecule usually has two antigen receptors and therefore contains 12 CDRs. The CDRs on the heavy and/or light chains may be separated by framework regions (FRs), which are less “variable” regions than the CDRs in the variable domains. For example, a chain (or each chain) may consist of four framework regions separated by three CDRs.

The sequences of the heavy and light chains of exemplary antibodies of the invention, comprising three different CDRs on the heavy chain and three different CDRs on the light chain, were determined. The positions of CDR amino acids are defined according to the IMGT numbering system (IMGT: http://www.imgt.org/; cf. Lefranc, M.-P. et al. (2009) Nucleic Acids Res. 37, D1006-D1012 ).

Table 1 below shows the sequence numbers of the amino acid sequences of the heavy chain CDRs (CDRH1, CDRH2 and CDRH3) and heavy chain variable regions (referred to as “VH”) of exemplary antibodies according to the invention: antibody name CDRH1 CDRH2 CDRH3 VH MGG1 28 29 30 35 MGG2 46 47 48 53 MGG3 64 65 66 71 MGG4 82 83 84 89 MGG8 100 101 102 107 MGH1 118 119 120 125 MGH2 136 137 138 143 MGH3 154 155 156 161 MGU1 172 173 174 178 MGU3 188 189 190 195 MGU5 206 207 208 213 MGU8 224 225 226 231 MGU10 242 243 244 248 MGU11 258 259 260 265 MGU12 276 277 278 283 MGV3 294 295 296 301

Table 1.

Table 2 below shows the sequence numbers of the amino acid sequences of the light chain CDRs (CDRL1, CDRL2 and CDRL3) and light chain variable regions (referred to as “VL”) of exemplary antibodies according to the invention: antibody name CDRL1 CDRL2 CDRL2 long CDRL3 V.L. MGG1 31 32 33 34 36 MGG2 49 50 51 52 54 MGG3 67 68 69 70 72 MGG4 85 86 87 88 90 MGG8 103 104 105 106 108 MGH1 121 122 123 124 126 MGH2 139 140 141 142 144 MGH3 157 158 159 160 162 MGU1 175 176 - 177 179 MGU3 191 192 193 194 196 MGU5 209 210 211 212 214 MGU8 227 228 229 230 232 MGU10 245 246 - 247 249 MGU11 261 262 263 264 266 MGU12 279 280 281 282 284 MGV3 297 298 299 300 302

Table 2.

Accordingly, the antibody, or antigen-binding fragment thereof, according to the invention has at least 70%, at least 75%, at least 80%, and an amino acid sequence having an identity of at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

Preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDR11, at least one CDRL2, at least one CDRL3. Comprising a light chain comprising, said at least one CDR, preferably at least one heavy chain CDRH3, is SEQ ID NO: 30, 48, 66, 84, 102, 120, 138, 156, 174, 190, 208, 226, 260 , 244, 278 and 296, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97 %, at least 98% or at least 99% sequence identity.

More preferably, the antibody, or antigen-binding fragment thereof according to the invention has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and at least one CDR11, at least one CDRL2, at least one CDRL3. It includes a light chain containing the above

(i) at least one heavy chain CDRH1 has an amino acid sequence according to SEQ ID NOs: 28, 46, 64, 82, 100, 118, 136, 154, 172, 188, 206, 224, 242, 258, 276, and 294, or Sequence identity of at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% Includes functional sequence variants thereof having;

(ii) at least one CDRH2 has an amino acid sequence according to SEQ ID NOs: 29, 47, 65, 83, 101, 119, 137, 155, 173, 189, 207, 225, 243, 259, 277, and 295, or at least sequence identity of 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% Includes functional sequence variants thereof; and/or

(iii) at least one heavy chain CDRH3 has an amino acid sequence according to SEQ ID NOs: 30, 48, 66, 84, 102, 120, 138, 156, 174, 190, 208, 226, 260, 244, 278 and 296, or at least sequence identity of 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% Includes functional sequence variants thereof.

The antibody, or antigen-binding fragment thereof, according to the invention has a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and a light chain comprising at least one CDRL1, at least one CDRL2 and at least one CDRL3. It is also desirable to include the above

(i) at least one CDRL1 has an amino acid sequence according to SEQ ID NOs: 31, 49, 67, 85, 103, 121, 139, 157, 175, 191, 209, 227, 245, 261, 279, and 297, or at least sequence identity of 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% Includes functional sequence variants thereof;

(ii) at least one CDRL2 has SEQ ID NO: 32, 33, 50, 51, 68, 69, 86, 87, 104, 105, 122, 123, 140, 141, 158, 159, 176, 192, 193, 210 , 211, 228, 229, 246, 262, 263, 280, 281, 298 and 299, or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, and functional sequence variants thereof having a sequence identity of at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%; and/or

(iii) at least one CDRL3 has an amino acid sequence according to SEQ ID NOs: 34, 52, 70, 88, 106, 124, 142, 160, 177, 194, 212, 230, 247, 264, 282, and 300, or at least sequence identity of 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% Includes functional sequence variants thereof.

Preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 64-66; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (ii) SEQ ID NO: 82 - 84; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (iii) SEQ ID NO: 136 - 138; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (iv) SEQ ID NO: 154 - 156; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (v) SEQ ID NO: 206 - 208; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (vi) SEQ ID NO: 224 - 226; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (vii) SEQ ID NO: 258 - 260; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (viii) SEQ ID NO: 276 - 278; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (ix) SEQ ID NO: 294 - 296; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (x) SEQ ID NO: 28 - 30; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (xi) SEQ ID NO: 46 - 48; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (xii) SEQ ID NO: 100 - 102; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (xiii) SEQ ID NO: 118 - 120; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (xiv) SEQ ID NO: 172 - 174; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (xv) SEQ ID NO: 188 - 190; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (xvi) SEQ ID NO: 242 - 244; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes CDRH1, CDRH2, and CDRH3 amino acid sequences along with their functional sequence variants having identity.

Preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 64 - 68 and 70; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (ii) SEQ ID NOs: 64 - 67 and 69 - 70; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (iii) SEQ ID NOs: 82 - 86 and 88; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (iv) SEQ ID NOs: 82 - 85 and 87 - 88; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (v) SEQ ID NOs: 136 - 140 and 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (vi) SEQ ID NOs: 136 - 139 and 141 - 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (vii) SEQ ID NOs: 154 - 158 and 160; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (viii) SEQ ID NOs: 154 - 157 and 159 - 160; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; (ix) SEQ ID NOs: 206 - 210 and 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (x) SEQ ID NOs: 206 - 209 and 211 - 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xi) SEQ ID NOs: 224 - 228 and 230; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xii) SEQ ID NOs: 224 - 227 and 229 - 230; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xiii) SEQ ID NOs: 258 - 262 and 264; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xiv) SEQ ID NOs: 258 - 261 and 263 - 264; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xv) SEQ ID NOs: 276 - 280 and 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xvi) SEQ ID NOs: 276 - 279 and 281 - 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xvii) SEQ ID NOs: 294 - 298 and 300; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xviii) SEQ ID NOs: 294 - 297 and 299 - 300; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xix) SEQ ID NOs: 28 - 32 and 34; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xx) SEQ ID NO: 28 - 31 and 33 - 34; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxi) SEQ ID NOs: 46 - 50 and 52; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxii) SEQ ID NOs: 46 - 49 and 51 - 52; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxiii) SEQ ID NO: 100 - 104 and 106; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxiv) SEQ ID NOs: 100 - 103 and 105 - 106; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxv) SEQ ID NOs: 118 - 122 and 124; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxvi) SEQ ID NOs: 118 - 121 and 123 - 124; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxvii) SEQ ID NOs: 172 - 176 and 178; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxviii) SEQ ID NO: 172 - 177; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxix) SEQ ID NOs: 188 - 192 and 194; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxx) SEQ ID NOs: 188 - 191 and 193 - 194; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (xxxi) SEQ ID NO: 242 - 247; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

More preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 64 - 68 and 70, respectively; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 64 - 67 and 69 - 70; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

More preferably, the antibody, or antigen-binding fragment thereof according to the invention has (i) SEQ ID NOs: 224 - 228 and 230; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 224 - 227 and 229 - 230; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Even more preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 276 - 280 and 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 276 - 279 and 281 - 282; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Even more preferably, the antibody, or antigen-binding fragment thereof according to the present invention has (i) SEQ ID NOs: 206 - 210 and 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 206 - 209 and 211 - 212; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Particularly preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) SEQ ID NOs: 136 - 140 and 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 136 - 139 and 141 - 142; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Most preferably, the antibody according to the invention, or antigen-binding fragment thereof, comprises (i) SEQ ID NOs: 82 - 86 and 88; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. according to its functional sequence variants having identity; or (ii) SEQ ID NOs: 82 - 85 and 87 - 88; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the sequence. Includes the CDRH1, CDRH2, and CDRH3 amino acid sequences and the CDRL1, CDRL2, and CDRL3 amino acid sequences along with their functional sequence variants having identity.

Moreover, the antibody, or antigen-binding fragment thereof according to the invention also comprises a heavy chain variable region (VH) and optionally a light chain variable region (VL), wherein the heavy chain variable region (VH) is SEQ ID NO: 35, 53, 71 , 89, 107, 125, 143, 161, 178, 195, 213, 231, 248, 265, 283, and 301; or at least 70%, at least 75%, at least 80%, at least 85%, It comprises or consists of a functional sequence variant thereof having a sequence identity of at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

Preferably, the antibody according to the invention, or antigen-binding fragment thereof, has (i) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 71 or at least 70%, at least 75%, at least 80%, at least 85%, A functional sequence variant thereof having a sequence identity of at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain according to SEQ ID NO: 72 Variable region (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% % or functional sequence variants thereof with sequence identity of at least 99%; (ii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 89 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 90 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; (iii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 143 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, A functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 144 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; (iv) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 161 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, A functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 162 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; or (v) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 213 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 214 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; (vi) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 231 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, A functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 232 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; (vii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 265 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 266 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; (viii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 283 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, A functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 284 or at least 70%, at least 75%, Includes functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and; or (ix) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 301 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 302 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; or (x) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO:35 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 36 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; or (xi) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 53 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , functional sequence variants thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 54 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; or (xii) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 107 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 108 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; or (xiii) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 125 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 126 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; or (xiv) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 178 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 179 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; or (xv) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 195 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 196 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Contains; or (xvi) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 248 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95% , a functional sequence variant thereof having a sequence identity of at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 249 or at least 70%, at least 75% , functional sequence variants thereof having a sequence identity of at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. Includes.

More preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 71 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 72. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

More preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 231 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 232. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

Even more preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 283 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%. %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 284. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

Even more preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 213, or at least 70%, at least 75%, at least 80%, at least 85%, at least A functional sequence variant thereof having a sequence identity of 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and/or a light chain variable according to SEQ ID NO: 214 region (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or a functional sequence variant thereof with at least 99% sequence identity.

Particularly preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 143 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 144. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

Most preferably, the antibody according to the invention, or antigen-binding fragment thereof, has a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 89 or at least 70%, at least 75%, at least 80%, at least 85%, at least 88 %, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity and/or a light chain variable region according to SEQ ID NO: 90. (VL) amino acid sequence or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98% or and functional sequence variants thereof with sequence identity of at least 99%.

Preferably, the antibody, or antigen-binding fragment thereof according to the invention is gMGG1, gMGG2, gMGG3, gMGG4, gMGG8, gMGH1, gMGH2, gMGH3, gMGU1, gMGU3, gMGU5, gMGU8, gMGU10, gMGU11, gMGU12 or gMGV3, preferably Preferably, the antibody, or antigen-binding fragment thereof, is gMGG3, gMGG4, gMGH2, gMGU5, gMGU8, or gMGU12, and more preferably, the antibody, or antigen-binding fragment thereof, is gMGG4 or gMGH2.

The present inventors have disclosed a monoclonal antibody (mAb) according to the invention, referred to herein as MGG1, MGG2, MGG3, MGG4, MGG8, MGH1, MGH2, MGH3, MGU1, MGU3, MGU5, MGU8, MGU10, MGU11, MGU12 and MGV3. ) was isolated (see Tables 1 and 2, Example 1). Based on these antibodies, especially their VH and VL genes, the terms used herein “gMGG1”, “gMGG2”, “gMGG3”, “gMGG4”, “gMGG8”, “gMGH1”, “gMGH2”, “ “gMGH3”, “gMGU1”, “gMGU3”, “gMGU5”, “gMGU8”, “gMGU10”, “gMGU11”, “gMGU12”, and “gMGV3” are each “generic” antibodies, or antigen-binding antibodies thereof. Refers to a fragment.

That is, “gMGG1” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 28, the CDRH2 amino acid sequence according to SEQ ID NO: 29, the CDRH3 amino acid sequence according to SEQ ID NO: 30, the CDRL1 amino acid sequence according to SEQ ID NO: 31, SEQ ID NO: 32 or an antibody having a CDRL2 amino acid sequence according to SEQ ID NO: 33, and a CDRL3 amino acid sequence according to SEQ ID NO: 34, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 35 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 36.

“gMGG2” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 46, the CDRH2 amino acid sequence according to SEQ ID NO: 47, the CDRH3 amino acid sequence according to SEQ ID NO: 48, the CDRL1 amino acid sequence according to SEQ ID NO: 49, SEQ ID NO: 50 or 51 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 52, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 53 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 54.

“gMGG3” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 64, the CDRH2 amino acid sequence according to SEQ ID NO: 65, the CDRH3 amino acid sequence according to SEQ ID NO: 66, the CDRL1 amino acid sequence according to SEQ ID NO: 67, SEQ ID NO: 68 or 69 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 70, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 71 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 72.

“gMGG4” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 82, the CDRH2 amino acid sequence according to SEQ ID NO: 83, the CDRH3 amino acid sequence according to SEQ ID NO: 84, the CDRL1 amino acid sequence according to SEQ ID NO: 85, SEQ ID NO: 86 or 87 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 88, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 89 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 90.

“gMGG8” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 100, the CDRH2 amino acid sequence according to SEQ ID NO: 101, the CDRH3 amino acid sequence according to SEQ ID NO: 102, the CDRL1 amino acid sequence according to SEQ ID NO: 103, SEQ ID NO: 104 or 105 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 106, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 107 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 108.

“gMGH1” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 118, the CDRH2 amino acid sequence according to SEQ ID NO: 119, the CDRH3 amino acid sequence according to SEQ ID NO: 120, the CDRL1 amino acid sequence according to SEQ ID NO: 121, SEQ ID NO: 122 or 123 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 124, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 125 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 126.

“gMGH2” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 136, the CDRH2 amino acid sequence according to SEQ ID NO: 137, the CDRH3 amino acid sequence according to SEQ ID NO: 138, the CDRL1 amino acid sequence according to SEQ ID NO: 139, SEQ ID NO: 140 or 141 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 142, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 143 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 144.

“gMGH3” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 154, the CDRH2 amino acid sequence according to SEQ ID NO: 155, the CDRH3 amino acid sequence according to SEQ ID NO: 156, the CDRL1 amino acid sequence according to SEQ ID NO: 157, SEQ ID NO: 158 or 159 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 160, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 161 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 162.

“gMGU1” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 172, the CDRH2 amino acid sequence according to SEQ ID NO: 173, the CDRH3 amino acid sequence according to SEQ ID NO: 174, the CDRL1 amino acid sequence according to SEQ ID NO: 175, the CDRH2 amino acid sequence according to SEQ ID NO: 176 refers to an antibody having a CDRL2 amino acid sequence, and a CDRL3 amino acid sequence according to SEQ ID NO: 177, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 178 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 179.

“gMGU3” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 188, the CDRH2 amino acid sequence according to SEQ ID NO: 189, the CDRH3 amino acid sequence according to SEQ ID NO: 190, the CDRL1 amino acid sequence according to SEQ ID NO: 191, SEQ ID NO: 192 or 193 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 194, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 195 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 196.

“gMGU5” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 206, the CDRH2 amino acid sequence according to SEQ ID NO: 207, the CDRH3 amino acid sequence according to SEQ ID NO: 208, the CDRL1 amino acid sequence according to SEQ ID NO: 209, SEQ ID NO: 210 or 211 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 212, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 213 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 214.

“gMGU8” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 224, the CDRH2 amino acid sequence according to SEQ ID NO: 225, the CDRH3 amino acid sequence according to SEQ ID NO: 226, the CDRL1 amino acid sequence according to SEQ ID NO: 227, SEQ ID NO: 228 or 229 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 230, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 231 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 232.

“gMGU10” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 242, the CDRH2 amino acid sequence according to SEQ ID NO: 243, the CDRH3 amino acid sequence according to SEQ ID NO: 244, the CDRL1 amino acid sequence according to SEQ ID NO: 245, the CDRH2 amino acid sequence according to SEQ ID NO: 246 refers to an antibody having a CDRL2 amino acid sequence, and a CDRL3 amino acid sequence according to SEQ ID NO: 247, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 248 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 249.

“gMGU11” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 258, the CDRH2 amino acid sequence according to SEQ ID NO: 259, the CDRH3 amino acid sequence according to SEQ ID NO: 260, the CDRL1 amino acid sequence according to SEQ ID NO: 261, SEQ ID NO: 262 or 263 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 264, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 265 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 266.

“gMGU12” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 276, the CDRH2 amino acid sequence according to SEQ ID NO: 277, the CDRH3 amino acid sequence according to SEQ ID NO: 278, the CDRL1 amino acid sequence according to SEQ ID NO: 279, SEQ ID NO: 280 or 281 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 282, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 283 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 284.

“gMGV3” refers to the CDRH1 amino acid sequence according to SEQ ID NO: 294, the CDRH2 amino acid sequence according to SEQ ID NO: 295, the CDRH3 amino acid sequence according to SEQ ID NO: 296, the CDRL1 amino acid sequence according to SEQ ID NO: 297, SEQ ID NO: 298 or 299 refers to an antibody having a CDRL2 amino acid sequence according to and a CDRL3 amino acid sequence according to SEQ ID NO: 300, or an antigen-binding fragment thereof. The heavy chain variable region (VH) preferably has an amino acid sequence according to SEQ ID NO: 301 and the light chain variable region (VL) preferably has an amino acid sequence according to SEQ ID NO: 302.

Optional additional features of antibodies

Antibodies of the invention (i.e., antibodies that bind Plasmodium falciparum sporozoites and antibodies that bind peptides of the invention), and antigen-binding fragments thereof, can be linked to, for example, drugs for delivery to the site of treatment or to cells of interest. It is bound to a detectable label that facilitates imaging of the region containing the . Methods for binding drugs and detectable labels to antibodies, such as imaging methods using detectable labels, are well known in the art to which the present invention pertains. Labeled antibodies can be used in a variety of assays using a wide range of labels. By attaching a detectable substance to the antibody, detection of the formation of an antibody-antigen complex can be facilitated, for example, between an antibody of the invention and an epitope of interest or between a peptide or protein according to the invention and an antibody. Suitable detection means include radionuclides, enzymes, coenzymes, fluorescers, chemiluminescers, chromogens, enzyme substrates or cofactors, enzyme inhibitors, prosthetic group complexes. , including the use of labels such as free radicals, particles, dyes, etc. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; Examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; Examples of suitable fluorescent substances include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinyl amine, Contains dansyl chloride or phycoerythrin; An example of a luminescent material is luminol; Examples of bioluminescent substances include luciferase, luciferin, and aequorin; Examples of suitable radioactive substances include 125I, 131I, 35S or 3H. These labeled reagents can be used in a variety of well-known assays such as radioimmunoassay, enzyme immunoassay, such as ELISA, fluorescent immunoassay, etc. Accordingly, labeled antibodies according to the invention may be described, for example, in US 3,766,162; US 3,791,932; US 3,817,837; and US 4,233,402.

Antibodies according to the invention may be conjugated to a cytotoxin, therapeutic agent, or therapeutic moiety such as a radioactive metal ion or radioisotope. Examples of radioactive isotopes include I-131, I-123, I-125, Y-90, Re-188, Re-186, At-211, Cu-67, Bi-212, Bi-213, Pd-109, Including, but not limited to, Tc-99, In-111, etc. These antibody conjugates can be used to modify a given biological response; The drug portion should not be construed as limited to classic chemotherapy agents. For example, the drug moiety can be a protein or polypeptide that possesses the desired biological activity. These proteins may include toxins such as, for example, abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin.

Techniques for conjugating such therapeutic moieties to antibodies are well known. For example, Arnon et al. (1985) “Monoclonal Antibodies for Immunotargeting of Drugs in Cancer Therapy,” in Monoclonal Antibodies and Cancer Therapy, ed. Reisfeld et al. (Alan R. Liss, Inc.), pp. 243-256; ed. Hellstrom et al. (1987) “Antibodies for Drug Delivery,” in Controlled Drug Delivery, ed. Robinson et al. (2d ed; Marcel Dekker, Inc.), pp. 623-653; Thorpe (1985) “Antibody Carriers of Cytotoxic Agents in Cancer Therapy: A Review,” in Monoclonal Antibodies '84: Biological and Clinical Applications, ed. Pinchera et al. pp. 475-506 (Editrice Kurtis, Milano, Italy, 1985); “Analysis, Results, and Future Prospective of the Therapeutic Use of Radiolabeled Antibodies in Cancer Therapy,” in Monoclonal Antibodies for Cancer Detection and Therapy, ed. Baldwin et al. (Academic Press, New York, 1985), pp. 303-316; and Thorpe et al. (1982) Immunol. Rev. See 62:119-158.

Alternatively, an antibody, or antibody fragment thereof, may be conjugated to a second antibody, or antibody fragment thereof, to form an antibody heterozygote as described in US 4,676,980. Additionally, a linker may be used between the label of the invention and the antibody, for example as described in US 4,831,175. The antibody, or antigen-binding fragment thereof, may be directly labeled with radioactive iodine, indium, yttrium, or other radioactive particles known in the art, for example as described in US 5,595,721. You can. Treatment is described for example in WO00/52031; It may consist of a combination of treatment with conjugated and non-conjugated antibodies administered simultaneously or subsequently, as described in WO00/52473.

Antibodies of the invention can also be attached to solid supports. Additionally, antibodies of the invention, or functional antibody fragments thereof, may be chemically modified, for example, by covalent conjugation with polymers to increase their circulating half-life. Examples of polymers and methods for attaching them to peptides are described in US 4,766,106; US 4,179,337; US 4,495,285 and US 4,609,546. In some embodiments, the polymer may be selected from polyoxyethylated polyol and polyethylene glycol (PEG). PEG is soluble in water at room temperature and has the general formula: R(O-CH2-CH2)nO-R where R can be hydrogen or a protecting group such as an alkyl or alkanol group. Preferably, the protecting group may have 1 to 8 carbons. For example, the protecting group is methyl. The symbol n is a positive integer. In one embodiment n is from 1 to 1,000. In other embodiments, n is from 2 to 500. Preferably, the PEG has an average molecular weight between 1,000 and 40,000, more preferably the PEG has an average molecular weight between 2,000 and 20,000, and even more preferably the PEG has an average molecular weight between 3,000 and 12,000. Additionally, PEG may have at least one hydroxy group, for example, PEG may have a terminal hydroxy group. For example, it is the terminal hydroxy group that is activated to react with the free amino group on the inhibitor. However, it will be appreciated that the type and amount of reactive groups may vary to achieve the covalently conjugated PEG/antibody of the invention.

Water-soluble polyoxyethylated polyols are also useful in the present invention. These include polyoxyethylated sorbitol, polyoxyethylated glucose, polyoxyethylated glycerol (POG), etc. In one embodiment, POG is used. Without being bound by theory, the glycerol backbone of polyoxyethylated glycerol is derived from mono-, di-, and triglycerides identical to those that occur naturally in animals and humans, for example. Because it is a backbone, these branches are not necessarily considered foreign substances in the body. POG can have a molecular weight in the same range as PEG. Another drug delivery system that can be used to increase circulating half-life is liposomes. Methods for preparing liposomal delivery systems are known to those skilled in the art. Other drug delivery systems are known in the art, see, for example, Poznansky MJ and Juliano RL, 1984, Pharmacol. Rev. 36(4): 277-336.

The antibodies of the present invention may be provided in purified form. Typically, the antibody will be present in a composition that is substantially free of other polypeptides, for example, less than 90% (by weight) of the composition consists of other polypeptides.

Antibodies of the invention may be immunogenic in non-human (or xenogeneic) hosts, such as mice. In particular, an antibody may have an idiotope that is immunogenic in non-human hosts but not in human hosts. In particular, antibodies of the invention for human use include antibodies that cannot be easily isolated from hosts such as mouse, goat, rabbit, rat, non-primate mammal, etc. and generally cannot be obtained from humanized or xeno-mouse. .

antibody production

The antibody according to the present invention can be produced by any method known in the art to which the present invention pertains. For example, the general method for producing monoclonal antibodies using hybridoma technology is well known (Kohler, G. and Milstein, C,. 1975; Kozbar et al. 1983).

Preferably, the EBV immortalization method described in WO2004/076677 is used. In this method, B cells producing antibodies of the invention are transformed with EBV and a polyclonal B cell activator. Additional stimulators of cell growth and differentiation can optionally be added during the transformation step to further improve efficiency. These stimulants may be cytokines such as IL-2 and IL-15. In one aspect, IL-2 is added during the immortalization step to further improve immortalization efficiency, but its use is not required. Immortalized B cells produced using these methods can therefore be cultured using methods known in the art and antibodies isolated therefrom.

Another preferred method is described in WO 2010/046775. In this method, plasma cells are cultured in limited numbers or as single plasma cells in microwell culture plates. Antibodies can be isolated from plasma cell cultures. Additionally, RNA can be extracted from the plasma cell culture and PCR can be performed using methods known in the art to which the present invention pertains. The VH and VL regions of the antibody can be amplified by RT-PCR (reverse transcriptase PCR), sequenced, cloned into an expression vector, and then transfected into HEK293T cells or other host cells. Cloning of nucleic acids in expression vectors, transfection of host cells, culturing of transfected host cells, and isolation of produced antibodies can be performed using any method known to those skilled in the art to which the present invention pertains. .

If necessary, antibodies can be further purified using various chromatographic methods such as filtration, centrifugation and HPLC or affinity chromatography. Techniques for purifying antibodies, such as monoclonal antibodies, including techniques for producing pharmaceutical grade antibodies, are well known in the art to which this invention pertains.

Fragments of antibodies of the invention can be obtained from antibodies by methods involving cleavage of disulfide bonds by chemical reduction and/or digestion by enzymes such as pepsin or papain. Alternatively, fragments of antibodies can be obtained by cloning and expression of portions of the heavy or light chain sequences. Antibody “fragments” include Fab, Fab', F(ab')2 and Fv fragments. The invention also includes single-chain Fv fragments (scFv) derived from the heavy and light chains of the antibodies of the invention. For example, the invention includes scFvs comprising CDRs from antibodies of the invention. Heavy or light chain monomers and dimers, single domain heavy chain antibodies, single domain light chain antibodies as well as single chain antibodies, such as single chain Fvs in which the heavy and light chain variable domains are linked by a peptide linker.

Antibody fragments of the invention may confer monovalent or multivalent interactions and may be incorporated into a variety of structures as described above. For example, scFv molecules can be synthesized to produce a trivalent “triabody” or a tetravalent “tetrabody”. The scFv molecule can contain domains of the Fc region to generate a bivalent minibody. Additionally, the sequence of the invention may be a component of a multispecific molecule, wherein the sequence of the invention targets an epitope of the invention and other regions of the molecule bind to different targets. Exemplary molecules include, but are not limited to, bispecific Fab2, trispecific Fab3, bispecific scFv, and diabody (Holliger and Hudson, 2005, Nature Biotechnology 9: 1126-1136).

Standard techniques in molecular biology can be used to prepare DNA sequences encoding antibodies or antibody fragments of the invention. The desired DNA sequence can be fully or partially synthesized using oligonucleotide synthesis techniques. Site-directed mutagenesis and polymerase chain reaction (PCR) techniques may be used as appropriate.

Any suitable host cell/vector system can be used for expression of the DNA sequences encoding the antibody molecules of the invention or fragments thereof. Bacteria, such as Escherichia coli, and other microbial systems can be used for the expression of antibody fragments, in part Fab and F(ab')2 fragments, and especially Fv fragments and single chain antibody fragments, such as single chain Fvs. there is. Eukaryotic, eg mammalian, host cell expression systems can be used for the production of larger antibody molecules, including intact antibody molecules. Suitable mammalian host cells include, but are not limited to, CHO, HEK293T, PER.C6, NS0, myeloma or hybridoma cells.

The present invention also includes the steps of culturing a host cell containing a vector encoding a nucleic acid of the present invention under conditions suitable for expression of a protein from the DNA encoding the antibody molecule of the present invention and isolating the antibody molecule. Provides a method for producing antibody molecules according to.

The antibody molecule may contain only heavy or light chain polypeptides, in which case only the heavy or light chain polypeptide coding sequences need be used to transfect the host cell. For production of a product comprising both heavy and light chains, a cell line can be transfected with two vectors, the first vector encoding the light chain polypeptide and the second vector encoding the heavy chain polypeptide. Alternatively, a single vector can be used, which contains sequences encoding light and heavy chain polypeptides. Alternatively, antibodies according to the invention may be produced by (i) expressing a nucleic acid sequence according to the invention in a host cell, for example using a vector according to the invention, and (ii) isolating the expressed antibody product. there is. Additionally, the method may include the step of (iii) purifying the isolated antibody. Transformed B cells and cultured plasma cells can be screened for those that produce antibodies of the desired specificity or function.

The screening step may be performed using any immunoassay, such as ELISA, staining of tissues or cells (including transfected cells), neutralization assay, or any method in the field to which the present invention pertains to confirm the desired specificity or function. It may be performed by one of a number of different methods known in the art. Assays can be selected based on simple recognition of one or more antigens, for example by selecting neutralizing antibodies rather than antigen-binding antibodies, or on signaling cascades, morphology, growth rate, ability to affect other cells, or Antibodies that can change the characteristics of target cells, such as response to influences by other reagents or changes in conditions, differentiation status, etc., can be selected based additionally on the desired function.

Individual transformed B cell clones can then be generated from the positive transformed B cell culture. Cloning steps to isolate individual clones from a mixture of positive cells may include limiting dilution, micromanipulation, single cell deposition by cell sorting, or other methods known in the art. It can be performed using a method.

Nucleic acids from cultured plasma cells can be isolated, cloned, and expressed in HEK293T cells or other known host cells using methods known in the art.

Immortalized B cell clones or transfected host cells of the invention can be used for research in a variety of ways, for example, as a source of monoclonal antibodies, as a source of nucleic acid (DNA or mRNA) encoding the monoclonal antibody of interest, etc. can be used for

The invention also provides compositions comprising immortalized B memory cells or transfected host cells producing an antibody according to the invention.

Immortalized B cell clones or cultured plasma cells of the invention can also be used as a source of nucleic acid for cloning antibody genes for subsequent recombinant expression. Expression from recombinant sources is more common for pharmaceutical purposes than expression from B cells or hybridomas for reasons such as stability, reproducibility, ease of culture, etc.

Accordingly, the present invention also provides a method comprising: (i) obtaining one or more nucleic acids (e.g., heavy and/or light chain mRNA) from a B cell clone or cultured plasma cells encoding an antibody of interest; (ii) inserting a nucleic acid into an expression vector and (iii) transfecting the vector into a host cell to allow expression of the antibody of interest in the host cell.

Similarly, the present invention provides a method for: (i) sequencing nucleic acid(s) from a B cell clone or cultured plasma cell encoding an antibody of interest; step; and (ii) using the sequence information from step (i) to prepare nucleic acid(s) for insertion into the host cell to allow expression of the antibody of interest in the host cell. do. The nucleic acid may, but need not, be manipulated between steps (i) and (ii) to introduce restriction sites, alter codon usage, and/or optimize transcriptional and/or translational control sequences.

Moreover, the invention also provides a method of making a transfected host cell comprising transfecting the host cell with one or more nucleic acids encoding an antibody of interest, wherein the nucleic acids are an immortalized B cell clone or It is a nucleic acid derived from cultured plasma cells of the invention. Accordingly, the procedure of first preparing the nucleic acid(s) and then using them to transfect host cells may be performed at different times by different people in different locations (e.g., different countries).

The recombinant cells of the present invention can then be used for expression and culture purposes. They are particularly useful for the expression of antibodies for large-scale pharmaceutical production. They can also be used as active ingredients in pharmaceutical compositions. Static culture, roller bottle culture, ascites fluid, hollow-fiber type bioreactor cartridge, modular minifermenter, stirred tank ), microcarrier culture, ceramic core perfusion, etc., any suitable culture technique can be used.

Methods for obtaining and sequencing immunoglobulin genes from B cells or plasma cells are well known in the art (see, for example, Chapter 4 of Kuby Immunology, 4th edition, 2000).

The transfected host cells include yeast and animal cells, especially mammalian cells (e.g., CHO cells, NS0 cells, human cells such as PER.C6 or HKB 11 cells, myeloma cells, or human liver cells). It may also be a eukaryotic cell, including plant cells, with mammalian cells being preferred. Preferred expression hosts are capable of glycosylating the antibodies of the invention, particularly carbohydrate structures that are not immunogenic in humans. In one embodiment, the transfected host cells can be grown in serum-free medium. In a further example, the transfected host cells can be grown in culture without the presence of animal-derived products. Transfected host cells can also be cultured to provide cell lines.

The present invention also provides a method comprising: (i) producing an immortalized B cell clone or culturing plasma cells according to the present invention; (ii) obtaining from a B cell clone or cultured plasma cell nucleic acid encoding the antibody of interest, a method of producing one or more nucleic acid molecules (e.g., heavy and light chain genes) encoding the antibody of interest to provide. Additionally, the present invention includes the steps of (i) producing an immortalized B cell clone or culturing a plasma cell according to the present invention; (ii) sequencing the nucleic acid from a B cell clone or cultured plasma cell encoding the antibody of interest.

The invention also provides a method of making nucleic acid molecule(s) encoding an antibody of interest, comprising obtaining nucleic acid from a transformed B cell clone or cultured plasma cell of the invention. Therefore, the procedure for first obtaining B cell clones or cultured plasma cells and then obtaining nucleic acid(s) from the B cell clones or cultured plasma cells may be performed at different times by different people in different places (e.g., different countries). It can be carried out in .

The invention also provides a method comprising: (i) obtaining and/or sequencing one or more nucleic acids (e.g., heavy and light chain genes); (ii) inserting nucleic acid(s) or using the nucleic acid(s) sequence(s) to prepare an expression vector; (iii) transfecting a host cell capable of expressing the antibody of interest; (iv) culturing or sub-culturing the transfected host cells under conditions that express the antibody of interest; and optionally, (v) purifying the antibody of interest.

The invention also provides preparation of an antibody comprising culturing or subculturing a population of transfected host cells, e.g., a population of stably transfected host cells, under conditions in which the antibody of interest is expressed, and optionally purifying the antibody of interest. A method is provided, wherein the transfected host cell population (i) provides nucleic acid(s) encoding a selected antibody of interest produced by a B cell clone or cultured plasma cell prepared as described above, (ii) Injecting the nucleic acid(s) into the expression vector, (iii) transfecting the vector in a host cell capable of expressing the antibody of interest, and (iv) generating the transfected host cell containing the inserted nucleic acid to produce the antibody of interest. It was prepared by culturing or subculturing. Accordingly, the procedure of first producing recombinant host cells and then culturing them to express the antibody may be performed by different people in different locations (e.g., in different countries) and at very different times.

Nucleic acid molecules, vectors and cells

In another aspect, the invention also provides a nucleic acid molecule comprising a polynucleotide encoding an antibody, or antigen-binding fragment thereof, according to the invention as described above. In another aspect, the invention also provides a nucleic acid molecule comprising a polynucleotide encoding a peptide according to the invention as described above or a protein according to the invention as described above.

Examples of nucleic acid molecules and/or polynucleotides include, for example, recombinant polynucleotides, vectors, oligonucleotides, RNA molecules such as rRNA, mRNA, miRNA, siRNA or tRNA, or DNA molecules such as cDNA molecules. The nucleic acid molecule can also be a vector as described below.

A nucleic acid molecule is a molecule that contains, and preferably consists of, nucleic acid components. The term nucleic acid molecule preferably refers to a DNA or RNA molecule. In particular, synonyms for the term “polynucleotide” are used. Preferably, the nucleic acid molecule is a polymer comprising or consisting of nucleotide monomers covalently linked to each other by phosphodiester-linkages of the sugar/phosphate-backbone. The term “nucleic acid molecule” also includes modified nucleic acid molecules, such as DNA or RNA molecules, such as base-modified, sugar-modified or backbone-modified.

With regard to nucleic acid molecules comprising polynucleotides encoding antibodies according to the invention, nucleic acid sequences encoding the light and heavy chains and part or all of the CDRs of the antibodies of the invention are preferred. Therefore, preferably provided herein are nucleic acid sequences encoding part or all of the light and heavy chains, especially the VH and VL sequences, and the CDRs of the antibodies of the invention. Tables 1 and 2 provide sequence numbers for the amino acid sequences of the VH and VL and CDRs of exemplary antibodies according to the invention.

Tables 3 and 4 below provide sequence numbers for exemplary nucleic acid sequences encoding the VH and VL and CDRs of exemplary antibodies according to the invention. Due to the redundancy of the genetic code, the invention also includes sequence variants of these nucleic acid sequences and especially those sequence variants encoding the same amino acid sequence.

Table 3 below shows the sequence numbers of the nucleic acid sequences of the heavy chain CDRs (CDRH1, CDRH2 and CDRH3) and heavy chain variable regions (referred to as “VH”) of exemplary antibodies according to the invention: antibody name CDRH1 CDRH2 CDRH3 VH MGG1 37 38 39 44 MGG2 55 56 57 62 MGG3 73 74 75 80 MGG4 91 92 93 98 MGG8 109 110 111 116 MGH1 127 128 129 134 MGH2 145 146 147 152 MGH3 163 164 165 170 MGU1 180 181 182 186 MGU3 197 198 199 204 MGU5 215 216 217 222 MGU8 233 234 235 240 MGU10 250 251 252 256 MGU11 267 268 269 274 MGU12 285 286 287 292 MGV3 303 304 305 310

Table 3.

Table 4 below shows the sequence numbers of the nucleic acid sequences of the light chain CDRs (CDRL1, CDRL2 and CDRL3) and light chain variable regions (referred to as “VL”) of exemplary antibodies according to the invention: antibody name CDRL1 CDRL2 CDRL2 long CDRL3 V.L. MGG1 40 41 42 43 45 MGG2 58 59 60 61 63 MGG3 76 77 78 79 81 MGG4 94 95 96 97 99 MGG8 112 113 114 115 117 MGH1 130 131 132 133 135 MGH2 148 149 150 151 153 MGH3 166 167 168 169 171 MGU1 183 184 - 185 187 MGU3 200 201 202 203 205 MGU5 218 219 220 221 223 MGU8 236 237 238 239 241 MGU10 253 254 - 255 257 MGU11 270 271 272 273 275 MGU12 288 289 290 291 293 MGV3 306 307 308 309 311

Table 4.

Preferably, the sequence of the nucleic acid molecule according to the invention is SEQ ID NO: 37 - 45, 55 - 63, 73 - 81, 91 - 99, 109 - 117, 127 - 135, 145 - 153, 163 - 171, 180 - A polynucleotide sequence according to any one of 187, 197 - 205, 215 - 223, 233 - 241, 250 - 257, 267 - 275, 285 - 293, 303 - 311; or a functional sequence variant thereof. In other words, the nucleic acid molecule according to the invention has SEQ ID NOs: 37 - 45, 55 - 63, 73 - 81, 91 - 99, 109 - 117, 127 - 135, 145 - 153, 163 -171, 180 - 187, 197 - A nucleic acid sequence according to any one of 205, 215 - 223, 233 - 241, 250 - 257, 267 - 275, 285 - 293, 303 - 311; or at least 70%, at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of It is preferred to include a polynucleotide sequence comprising or consisting of a functional sequence variant thereof having sequence identity.

Nucleic acid sequences according to the invention may also be at least 70% relative to nucleic acids encoding CDRs, VH sequences and/or VL sequences used in (example) antibodies according to the invention, for example for the sequences shown in Tables 3 and 4. , a nucleic acid sequence having at least 75%, at least 80%, at least 85%, at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity. It is desirable to include.

A nucleic acid sequence according to the invention may also be a nucleic acid encoding a peptide according to the invention, for example at least 70%, at least 75%, at least 80%, at least 85% of the sequence according to any one of SEQ ID NOs: 1 - 24, It is preferred to include nucleic acid sequences having at least 88%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity. More preferably, the nucleic acid molecule according to the invention comprises a polynucleotide encoding any amino acid sequence according to any of SEQ ID NOs: 1 - 24.

In general, nucleic acid molecules can be manipulated to insert, delete, or alter specific nucleic acid sequences. Changes from these manipulations include, but are not limited to, changes to introduce restriction sites, modify codon usage, add or optimize transcriptional and/or translational control sequences, etc. It is also possible to alter nucleic acids to change the encoded amino acids. For example, introducing one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) amino acid substitutions, deletions and/or insertions into the amino acid sequence of the antibody. It can be useful. These point mutations can modify effector function, antigen-binding affinity, post-translational modifications, immunogenicity, etc., introduce amino acids for attachment of covalent groups (e.g. labels) (e.g. , for purification purposes) tags can be introduced. Mutations may be introduced at specific sites or may be introduced randomly and then selected (e.g., molecular evolution). For example, one or more nucleic acids encoding any of the CDR regions, VH sequences and/or VL sequences of an (example) antibody of the invention may be randomly or directionally mutated to introduce different properties into the encoded amino acids. there is. These changes may be the result of an iterative process in which the initial change is maintained and new changes are introduced at other nucleotide positions. Additionally, changes achieved in independent steps can be combined. Different properties introduced into the encoded amino acid may include, but are not limited to, enhanced affinity.

In another aspect, the invention also provides a vector comprising a nucleic acid molecule according to the invention, such as an expression vector. Preferably, the vector comprises a nucleic acid molecule as described above.

The term “vector” refers to a nucleic acid molecule, preferably a recombinant nucleic acid molecule, i.e., a nucleic acid molecule that does not occur in nature. Vectors in the context of the present invention are suitable for integrating or carrying the desired nucleic acid sequence. These vectors may be storage vectors, expression vectors, cloning vectors, transfer vectors, etc. A storage vector is a vector that allows convenient storage of nucleic acid molecules. Accordingly, the vector may comprise, for example, a sequence corresponding to the desired antibody or antibody fragment thereof according to the invention or to the desired peptide or protein according to the invention. Expression vectors can be used for the production of RNA, mRNA, or expression products such as peptides, polypeptides, or proteins. For example, an expression vector may contain sequences necessary for transcription of a stretch of sequence in the vector, such as a promoter sequence. Cloning vectors are typically vectors that contain cloning sites, which can be used to integrate nucleic acid sequences into the vector. Cloning vectors may be, for example, plasmid vectors or bacteriophage vectors. A transfer vector may be a vector suitable for transferring a nucleic acid molecule into a cell or organism, such as a viral vector. The vector in the context of the present invention may be, for example, an RNA vector or a DNA vector. Preferably, the vector is a DNA molecule. For example, a vector within the meaning of this application includes sequences suitable for propagation of the vector, such as a cloning site, a selection marker such as an antibiotic resistance factor, and an origin of replication. Preferably, in the context of the present application the vector is a plasmid vector.

In a further aspect, the invention also provides a method for (a) expressing (i) an antibody according to the invention, or antigen-binding fragment thereof, or (ii) a peptide or protein according to the invention; (b) Provides cells containing the vector according to the present invention.

Examples of such cells include, but are not limited to, eukaryotic cells, such as yeast cells, animal cells, or plant cells. Preferably, the cells are mammalian cells, more preferably mammalian cell lines. Preferred examples include human cells, CHO cells, HEK293T cells, PER.C6 cells, NS0 cells, human liver cells, myeloma cells or hybridoma cells.

In particular, cells can be transfected with a vector according to the invention, preferably an expression vector. The term “transfection” refers to the introduction of a nucleic acid molecule, such as DNA or RNA (e.g., mRNA), into a cell, preferably a eukaryotic cell. In the context of the present invention, the term "transfection" includes any method known to the person skilled in the art for introducing a nucleic acid molecule into a cell, preferably a eukaryotic cell such as a mammalian cell. . These methods include, for example, electroporation, lipofection, for example based on cationic lipids and/or liposomes, calcium phosphate precipitation, nanoparticle-based transfection. , virus-based transfection, or cationic polymer-based transfection, such as DEAE-dextran or polyethylenimine. Preferably, introduction is non-viral.

Additionally, cells of the invention can be stably or transiently transfected with a vector according to the invention, for example to express an antibody according to the invention, or an antigen-binding fragment thereof, or to express a peptide or protein according to the invention. It can be. Preferably, the cells are stably transfected with a vector according to the invention, for example encoding an antibody according to the invention, or an antigen-binding fragment thereof, or encoding a peptide or protein according to the invention. Alternatively, the cells are preferably transiently transfected with a vector according to the invention, for example encoding an antibody according to the invention, or an antigen-binding fragment thereof, or encoding a peptide or protein according to the invention.

pharmaceutical composition

In a further aspect, the present invention provides a pharmaceutical composition comprising one or more of the following:

(i) a peptide according to the invention;

(ii) a protein according to the invention;

(iii) a nucleic acid encoding a protein or peptide according to the invention;

(iv) virus-like particles according to the invention;

(v) protein nanoparticles according to the present invention;

(vi) an antibody according to the invention, or an antibody fragment thereof;

(vii) a nucleic acid encoding an antibody, or antibody fragment according to the invention;

(viii) a vector comprising a nucleic acid according to the invention; and/or

(ix) A cell expressing an antibody or peptide according to the present invention or containing a vector according to the present invention.

That is, the present invention also provides a peptide according to the present invention, a protein according to the present invention, a virus-like particle according to the present invention, a protein nanoparticle according to the present invention, an antibody according to the present invention, or an antigen-binding fragment thereof, according to the present invention. A pharmaceutical composition comprising a nucleic acid according to the present invention, a vector according to the present invention and/or a cell according to the present invention is provided.

Preferably, the pharmaceutical composition comprises a peptide according to the invention and/or a protein according to the invention.

The pharmaceutical composition preferably also comprises virus-like particles according to the invention and/or protein nanoparticles according to the invention.

In this regard, i.e. if the pharmaceutical composition comprises a peptide according to the invention, a protein according to the invention, a virus-like particle according to the invention and/or a protein nanoparticle according to the invention, the pharmaceutical composition Preferably it is a vaccine. “Vaccine” is understood to be a prophylactic or therapeutic substance that typically presents at least one antigen, preferably an immunogen, such as a peptide according to the invention. An “immunogen” is typically capable of triggering an immune response. As used herein, “immunogen” refers particularly to mammals (e.g. humans and cattle, preferably cattle), e.g. mammals that are infected or at risk of infection with pathogens (such as malaria parasites). It is a protein or part thereof that can induce an immune response. Administration of an immunogen may, for example, result in protective immunity and/or prior immunity to the pathogen of interest. Accordingly, an antigen or immunogen can typically stimulate the body's adaptive immune system to provide an adaptive immune response. In particular, an “antigen” or “immunogen” can typically be recognized by the immune system, preferably the adaptive immune system, for example by the formation of antibodies and/or antigen-specific T cells as part of an adaptive immune response. -Refers to a substance that can induce a specific immune response. Typically, the antigen may be or comprise a peptide or protein that can be presented to T-cells by MHC.

Preferably, the pharmaceutical composition comprises an antibody according to the invention, or an antibody fragment thereof.

It is also preferred that the composition comprises a nucleic acid according to the invention.

Preferably, the pharmaceutical composition comprises a vector according to the invention and/or a cell according to the invention.

The pharmaceutical composition may preferably include pharmaceutically acceptable carriers, diluents and/or excipients. A carrier or excipient may facilitate administration, but preferably should not induce the production of antibodies harmful to the individual receiving the composition itself. It must not be toxic either. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, and inactive viral particles. Generally, the pharmaceutically acceptable carrier in the pharmaceutical composition according to the present invention may be an active ingredient or an inactive ingredient. Preferably, the pharmaceutically acceptable carrier in the pharmaceutical composition according to the invention is not an active ingredient with respect to malaria.

Pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, inorganic acid salts such as phosphates and sulphates, or acetate, propionate, Salts of organic acids such as malonate and benzoate may be used.

Pharmaceutically acceptable carriers in pharmaceutical compositions may further include liquids such as water, saline, glycerol, and ethanol. Additionally, auxiliary substances such as wetting or emulsifying agents or pH buffering substances may be present in these compositions. These carriers allow the pharmaceutical composition to be formulated into tablets, pills, confections, capsules, liquids, gels, syrups, slurries and suspensions for ingestion by a subject.

The pharmaceutical composition of the present invention can be prepared in various forms. For example, the composition can be prepared as an injection as a liquid solution or suspension. Solid forms suitable for solution or suspension in a liquid vehicle prior to injection can also be prepared (e.g., lyophilized compositions similar to Synagis™ and Herceptin™ for reconstitution with sterile water containing a preservative). The composition may be prepared for topical administration, for example as an ointment, cream or powder. The compositions may be prepared for oral administration, for example as tablets or capsules, sprays or syrups (optionally flavored). The composition may be prepared for pulmonary administration using a fine powder or spray, for example as an inhaler. The composition can be prepared as a suppository or vaginal suppository. The composition may be prepared as, for example, drops for nasal, aural or ocular administration. The composition may be in the form of a kit designed to allow the combined composition to be reconstituted immediately prior to administration to a subject. For example, lyophilized antibodies may be provided in kit form along with sterilized water or sterile buffer.

The active ingredient in the composition is preferably an antibody according to the present invention, or an antibody fragment thereof. The active ingredient in the composition is preferably a peptide according to the invention, a protein according to the invention, a protein nanoparticle according to the invention and/or a virus-like particle according to the invention. Therefore, they (antibodies, peptides, proteins, etc.) may be susceptible to degradation in the gastrointestinal tract. Accordingly, when the composition is administered by a route using the gastrointestinal tract, the composition may contain an agent that protects the antibody, peptide, protein, protein nanoparticle, or virus-like particle from degradation but releases the composition upon absorption from the gastrointestinal tract.

A detailed discussion of pharmaceutically acceptable carriers is available in Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20th edition, ISBN: 0683306472.

Pharmaceutical compositions of the invention generally have a pH of between 5.5 and 8.5, in some embodiments this may be between 6 and 8, and in other embodiments around 7. pH can be maintained using buffer solutions. The composition may be sterile and/or pyrogen free. The composition may be isotonic to humans. In one embodiment, the pharmaceutical composition of the invention is supplied in a hermetically-sealed container.

Compositions in several forms of administration are within the scope of the present invention; Forms include, but are not limited to, forms suitable for parenteral administration, such as injection or infusion, such as bolus injection or continuous infusion. If the product is intended for injection or infusion, it may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulatory agents such as suspending agents, preservatives, stabilizers and/or dispersing agents. You can. Alternatively, the antibody or peptide/protein may be in dried form for reconstitution prior to use with an appropriate sterilizing liquid. A vehicle is typically understood to be a substance suitable for storing, transporting and/or administering a compound, such as a pharmaceutically active compound, in particular an antibody or peptide/protein according to the invention. For example, the vehicle may be a physiologically acceptable liquid, which is suitable for storing, transporting and/or administering a pharmaceutically active compound, especially an antibody or peptide/protein according to the invention. Once formulated, the compositions of the invention can be administered directly to a subject. In one embodiment, the composition is suitable for administration to a mammal, such as a human subject.

The pharmaceutical composition of the present invention can be administered orally, intravenously, intramuscularly, intraarterially, intramedullary, intraperitoneally, intrathecally, intraventricularly, transdermal, transcutaneous, topically, subcutaneously, intranasally, enterally, sublingually. It can be administered by any number of routes, including, but not limited to, intravaginal, or rectal routes. Hypospray can also be used to administer the pharmaceutical compositions of the present invention. Preferably, the pharmaceutical composition can be prepared for oral administration, for example as tablets, capsules, etc., for topical administration, or for injection, for example as a liquid solution or suspension, whereby it is particularly preferred that the pharmaceutical composition is injectable. do. It is also preferred that the pharmaceutical composition is in solid form suitable for solution or suspension in a liquid vehicle prior to injection, for example in lyophilized form.

For injection, for example intravenous, dermal or subcutaneous injection, or injection into painful areas, the active ingredient will preferably be in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has an appropriate pH, isotonicity and stability. . A person skilled in the art to which the present invention pertains will be able to prepare a suitable solution using an isotonic vehicle such as, for example, Sodium Chloride Injection, Ringer's Injection, and Lactated Ringer's Injection. You can. Preservatives, stabilizers, buffering agents, antioxidants and/or other additives may be included as needed. Whether a polypeptide, peptide or nucleic acid molecule or other pharmaceutically useful compound according to the invention to be provided to an individual, administration is preferably in a "prophylactically effective amount" or a "therapeutically effective amount" as (as the case may be) shown to be of benefit to the individual. It may be enough. The actual dosage, rate of administration, and time course of administration will vary depending on the nature and severity of the subject being treated. For injection, the pharmaceutical composition according to the invention may be presented, for example, in a prefilled syringe.

The pharmaceutical compositions of the invention as defined above may also be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is desired for oral use, the active ingredient, i.e. the transporter cargo conjugate molecule of the invention as defined above, is combined with emulsifying agents and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

The pharmaceutical compositions of the invention may also be administered topically, especially when the subject of treatment involves an area or organ that is readily accessible by topical administration, such as a disease of the skin or any other accessible epithelial tissue. . Topical preparations suitable for each of these areas or organs are readily prepared. For topical administration, the pharmaceutical composition of the invention may be formulated in a suitable ointment, suspending or dissolving it in one or more carriers comprising the pharmaceutical composition of the invention, especially the ingredients as defined above. Carriers for topical administration include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Included, but not limited to this. Alternatively, the pharmaceutical compositions of the present invention may be formulated in a suitable lotion or cream. In the context of the present invention, suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 -Includes, but is not limited to, octyldodecanol (2-octyldodecanol), benzyl alcohol, and water.

Dosage treatment may be a single dose schedule or a multiple dose schedule. In particular, the pharmaceutical composition may be provided as a single dose product. Preferably, the amount of antibody or peptide/protein in the pharmaceutical composition - especially when provided as a single dose product - does not exceed 200 mg, more preferably does not exceed 100 mg and even more preferably 50 mg. do not exceed

The pharmaceutical composition according to the present invention can be administered once or repeatedly. For example, the pharmaceutical composition according to the invention can be administered daily, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. , for 18, 19, 20, or 21 days or more, for example, every day, once or several times a day, for 1, 2, 3, 4, 5, or 6 months, for example, once or twice a day , may be administered three or four times, preferably once or twice a day, more preferably once a day. Preferably, the pharmaceutical composition according to the invention is administered weekly, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. , for 18, 19, 20 or 21 weeks or more, for example weekly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or 2,3,4, Alternatively, it may be administered weekly, once or twice per week for 5 years. Additionally, the pharmaceutical composition according to the invention may preferably be administered monthly, for example once a month, or more preferably monthly for 1, 2, 3, 4, or 5 years or more. It is also desirable for administration to continue throughout life. Additionally, only one single administration is also envisaged in relation to a specific indication, for example for malaria prophylaxis in non-immune subjects, for example in case of accidental exposure.

In particular, for single doses, e.g. daily, weekly or monthly doses, preferably weekly doses, the amount of antibody or peptide/protein in the pharmaceutical composition according to the invention does not exceed 1 g, preferably 500 mg. It is preferred not to exceed, more preferably not to exceed 200 mg, even more preferably not to exceed 100 mg, and particularly preferably not to exceed 50 mg.

Pharmaceutical compositions typically contain an “effective” amount of an antibody of the invention, or a peptide/protein of the invention, i.e. sufficient to treat, ameliorate, attenuate or prevent the desired disease or condition, or sufficient to produce a detectable therapeutic effect. Includes sheep. The therapeutic effect also includes reduction or attenuation of pathogenic capacity or physical symptoms. The exact effective amount for any particular subject will depend on their size, weight, and degree of health, nature, and condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The effective dose for a given situation is determined by routine experimentation and depends on the judgment of the clinician. For purposes of the present invention, an effective dose is generally from about 0.005 to about 100% of the antibody of the invention (e.g., the amount of antibody in a pharmaceutical composition) relative to the body weight (e.g., kg) of the subject being administered. mg/kg, preferably about 0.0075 to about 50 mg/kg, more preferably about 0.01 to about 10 mg/kg, even more preferably about 0.02 to about 5 mg/kg.

Additionally, the pharmaceutical composition according to the invention may comprise additional active ingredients, which may be additional antibodies or may be non-antibody components. The additional active ingredient is preferably a checkpoint inhibitor.

The antibody, or antigen-binding fragment according to the invention and/or the peptide/protein according to the invention may be present in the same pharmaceutical composition with additional active ingredients, or may preferably consist of a first pharmaceutical composition and further The active ingredient consists of a second pharmaceutical composition that is different from the first pharmaceutical composition. Therefore, when more than one additional active ingredient is envisaged, each additional active ingredient and the antibody or antigen-binding fragment according to the invention or the peptide/protein according to the invention preferably consist of a different pharmaceutical composition. These different pharmaceutical compositions may be administered in combination/simultaneously or at separate times or locations (e.g., separate parts of the body).

Preferably, the antibody (or peptide/protein) according to the invention and the further active ingredient provide an additive therapeutic effect or, preferably, a synergistic therapeutic effect. The term “synergy” is used to describe the combined effect of two or more active agents that is greater than the sum of the individual effects of each individual active agent. Accordingly, when the combined effect of two or more agents results in a “synergistic inhibition” or process of activity, the inhibition or process of activity is intended to be greater than the sum of the inhibitory effects of each individual active agent. The term “synergistic treatment effect” refers to the treatment effect observed with the combination of two or more therapies, wherein the treatment effect (measured by any of several parameters) is greater than that observed with each treatment individually. greater than the sum of its effects.

In one embodiment, a composition of the invention may comprise an antibody of the invention, wherein the antibody comprises at least 50% (e.g., 60%, 70%, 75%, 80%, 85%) by weight of the total protein in the composition. %, 90%, 95%, 96%, 97%, 98%, 99% or more). In such compositions, the antibody is preferably in purified form.

In another embodiment, a composition of the invention may comprise a peptide/protein of the invention, wherein the peptide/protein comprises at least 50% (e.g., 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more). In these compositions, the peptides/proteins are preferably in purified form.

The present invention also provides a method comprising: (i) preparing an antibody or peptide/protein of the present invention; and (ii) mixing the purified antibody or purified peptide/protein with one or more pharmaceutically acceptable carriers.

In another embodiment, a method of preparing a pharmaceutical composition includes mixing an antibody with one or more pharmaceutically acceptable carriers, wherein the antibody is obtained from transformed B cells or cultured plasma cells of the present invention. It is a monoclonal antibody.

As an alternative to delivering antibodies or B cells for therapeutic purposes, nucleic acids (typically DNA) encoding the antibodies or peptides/proteins can be delivered to the subject so that the nucleic acids are placed at that location in the subject to provide the desired therapeutic effect. It can be expressed in situ. Suitable gene therapy and nucleic acid transfer vectors are known in the art.

Pharmaceutical compositions may contain antibacterial agents, especially when packaged in multi-dose form. These may include detergents, for example Tween(polysorbate) such as Tween 80. Detergents are generally present at low levels, for example less than 0.01%. The composition may also include a sodium salt (eg, sodium chloride) to provide tonicity. For example, a concentration of 10 ± 2 mg/ml NaCl is typical.

Additionally, the pharmaceutical compositions may contain about 15-30 mg/ml (e.g. 25 mg/ml) of a sugar alcohol (e.g. For example, it may include mannitol) or a disaccharide (e.g., sucrose or trehalose). The pH of the composition for freeze-drying may be adjusted to 5 to 8, or 5.5 to 7, or about 6.1 before freeze-drying.

Compositions of the present invention may also include one or more immunomodulatory agents. Generally, immunomodulators include adjuvants. Therefore, especially in the case of vaccines, it is desirable for the pharmaceutical composition to contain an adjuvant. Examples of adjuvants include aluminum hydroxide (ALHYDROGEL®, available from Brenntag Biosector, Copenhagen, Denmark and AMPHOGEL®, Wyeth Laboratories, Madison, NJ), Freund's adjuvant, MPL?? (3-0-deacylated monophosphoryl lipid A; Corixa, Hamilton, IN), IL-12 (Genetics Institute, Cambridge, MA), TLR agonists (such as TLR-9 agonists), and QS-21 (Kiraya tree (soap) Bark tree (Purified plant extract from Quillaja saponaria ).

As used herein, the term “adjuvant” refers specifically to a vehicle used to enhance antigenicity/immunogenicity. Adjuvants include suspensions of minerals (alum, aluminum hydroxide, or phosphate) onto which antigens have been adsorbed; Or, for example, the antigen solution is emulsified in mineral oil (Freund incomplete adjuvant), sometimes to further enhance antigenicity (inhibiting the degradation of the antigen and/or triggering the influx of macrophages). ) Contains a water-in-oil emulsion containing killed mycobacteria. Immunostimulatory oligonucleotides (such as those containing CpG motifs) can also be used as adjuvants. Adjuvants include biological molecules, such as costimulatory molecules (“biological adjuvants”). Exemplary adjuvants include IL-2, RANTES, GM-CSF, TNF-a, IFN-y, G-CSF, LFA-3, CD72, B7-1, B7-2, OX-40L, 4-IBBL and TLR- Includes toll-like receptor (TLR) agonists such as 9 agonists. Those skilled in the art are familiar with adjuvants, e.g., adjuvants that may be included in pharmaceutical compositions (see, e.g., Singh (ed.) Vaccine Adjuvants and Delivery Systems. Wiley-Interscience, 2007) . Preferably, the adjuvant is selected to induce a Th1 immune response in the subject administered the pharmaceutical composition. In other words, the adjuvant included in the pharmaceutical composition preferably promotes a Th1 immune response. Preferably, the adjuvant is an alum, an oil-in water composition, MF59, ASO1, AS03, AS04, MPL, QS21, CpG oligonucleotide, TLR7 agonist, TLR4 agonist, TLR3 agonist, or two or more thereof. It's a combination.

Adjuvants may be selected from the group comprising mineral salts, surface active agents, micro particles, cytokines, hormones, antigenic structures, polyanions, polyacrylics or water-in-oil emulsions. Accordingly, the compositions of the present invention may include one or more adjuvants, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more adjuvants. For example, the composition of the present invention contains aluminum (“Alum”), aluminum hydroxide, aluminum phosphate, calcium phosphate, nonionic block polymer surfactant, virosome, saponin ( saponin (QS-21), meningococcal outer membrane protein (Proteosomes), immunostimulatory complexes (ISCOMs), cochleate Dimethyl dioctadecyl ammonium bromide (DDA), Avridine (CP20,961), vitamin A, vitamin E, cell wall skeleton of Mycobacterium phlei (Detox®), muramyl dipeptide and tripeptide (tripeptide), Threonyl MDP (SAF-1), Butyl-ester MDP (Murabutide®), Dipalmitoyl phosphatidylethanolamine MTP, monophosphoryl lipid A (Monophosphoryl lipid A), Klebsiella pneumonia glycoprotein, Bordetella pertussis , Bacillus Calmette-Guerin, Vibrio cholerae and Escherichia coli heat labile enterotoxin, trehalose dimycolate, CpG oligodeoxynucleotide, interleukin-2, interferon-γ, interferon-β, granulocyte-macrophage colony stimulating factor, dehydroepiandrosterone, Flt3 ligand, 1,25-di Hydroxyvitamin D3, interleukin-1, interleukin-6, interleukin-12, human growth hormone, 2-microglobulin, lymphotactin, polyanions such as dextran, double-stranded polynucleotides (double-stranded polynucleotide), polyacrylic, for example polymethylmethacrylate, acrylic acid cross-linked with allyl sucrose (Carbopol 934P), or for example N-acetyl-glucosamine-3yl-acetyl-L-alanyl-D-isoglutamine (CGP-11637), gamma inulin ) + aluminum hydroxide (Algammulin), human dendritic cells, lysophosphatidyl glycerol, stearyl tyrosine, tripalmitoyl pentapeptide, Carbopol 974P NF Polymer, water-in-oil emulsion, mineral oil (Freund's incomplete), vegetable oil (peanut oil), squalene and squalane, oil-in-water emulsion, squalene + Tween-80 + Span 85 (MF59), or for example liposomes, or for example biodegradable polymer microspheres, lactide and glycolide, polyphosphazene, beta-glucan, or for example proteinoids ( may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more adjuvants selected from proteinoids. A list of commonly used vaccine adjuvants can also be found in "Vaccine Adjuvants" edited by DT O'Hogan, Humana Press 2000. Adjuvants included in the compositions of the invention may also include, for example, synthetic derivatives of lipid A, some of which are TLR-4 agonists, such as OM174 (2-deoxy-6-o-[2-deoxy -2-[(R)-3-Dodecanoyloxytetra-decanoyl amino]-4-o-phosphono-DD-glucopyranosyl]-2-[(R)-3-hydroxy-tetradecanoyl amino]-pD-glucopyranosyldihydrogen-phosphate), (WO 95/14026) OM-294-DP (3S, 9R)-3~[(R)-dodecanoyloxytetradecanoylam, [( R)-3-hydroxytetradecanoylamino]decane-1,10-diol, 1,10-bis(dihydrogenophosphate) (WO 99/64301 and WO 00/0462) OM 197 MP-Ac DP(3S -, 9R)-3-D(R)-dodecanoyl-oxytetradecanoylamino]-4-oxo-5-aza-9-[(R)-3-hydroxytetra-decanoylamino] decane- Including, but not limited to, 1,10-diol, 1-dihydrogenophosphate-10-(6-aminohexanoate) (WO 01/46127). For example, the vaccine of the invention may contain only one of the above adjuvants, or a combination adjuvant, for example two of the above adjuvants, for example alum and MPL, or an oil-in-water emulsion and MPL and QS-21, or liposomes and May include MPL and QS21.

The vaccine according to the invention preferably comprises an adjuvant selected from the group comprising Alum, Ribi (monophosphoryl lipid A (MPL)), or MF59. Accordingly, the vaccine composition of the present invention comprises alum, or Livy (monophosphoryl lipid A, MPL), or MF59, or for example alum and Livy, or for example alum and MF59, or for example Livy and MF59 can do.

Particularly preferred adjuvants are non-toxic bacterial lipopolysaccharide derivatives. A preferred example of a suitable non-toxic derivative of lipid A is monophosphoryl lipid A (MPL), or more particularly 3-deacylated monophosphoryl lipid A (3DMPL). See, for example, US Patent No. 4,436,727; No. 4,877,611; See Nos. 4,866,034 and 4,912,094. MPL primarily promotes CD4+ T cell responses with an IFN-y (Th1) phenotype. In pharmaceutical compositions, for example, small particles 3D-MPL can be used. Small particle 3D-MPL has a particle size that can be sterile-filtered through a 0.22 μm filter. These preparations are described in WO 94/21292. Alternatively, the lipopolysaccharide may be B(1-6)glucosamine disaccharide, as described in US Patent No. 6,005,099 and European Patent No. 0 729 473 B1. A person skilled in the art to which the present invention pertains will be able to easily produce various lipopolysaccharides such as 3D-MPL based on the teachings of these references.

In addition to the above-mentioned immunostimulants (which are similar in structure to that of LPS or MPL or 3D-MPL), acylated monosaccharide and disaccharide derivatives that are subparts of the above structure of MPL are also suitable adjuvants.

Other particularly preferred adjuvants that can be used in pharmaceutical compositions are saponins such as QS21. QS-21 is a soap bark tree Quillaja saponaria (Zhu W. and Tuo W., 2016, Nat Prod Chem Res 3(4): e113. QS-21: A potent vaccine It is one of the active moieties derived from adjuvant. QS indicates its origin as Q. saponaria and the number 21 as the identity of the RP-HPLC peak. QS-21 is an acylated 3,28-bisdesmodic triterpene glycoside (1,3) (3, 28-bisdesmodic triterpene glycosides (1,3)) or “saponin” with molecular formula C92O46H148 and molecular weight 1990 Da. Saponins such as QS-21 can preferably be used as adjuvants, for example for systemic administration. The use of saponins as adjuvants (e.g. the use of Quil A derived from the bark of the South American tree Quillaja Saponaria Molina) is familiar to those skilled in the art (e.g. US 5,057,540 and EP 0 362 279 B1. EP 0 109 942 B1; WO 96/11711; WO 96/33739). The hemolytic saponins QS21 and QS17 (HPLC purified fraction of Quil A) have been described as potent systemic adjuvants, and methods for their production are disclosed in US Patent No. 4,087,096 and European Patent No. 0 362279 B1.

Preferably, the pharmaceutical composition comprises monophosphoryl lipid A (MPL) and/or saponins such as QS-21.

It is also preferred that toll-like receptor (TLR) agonists are used as adjuvants. For example, the pharmaceutical composition may include a TLR agonist. For example, TLR agonists include synthetic derivatives of lipid A (see, e.g., WO 95/14026 and WO 01/46127) alkyl Glucosaminide phosphate (AGP; e.g., WO 98/50399 or US It may be a TLR-4 agonist such as (see Patent Nos. 6,303,347; 6,764,840). Other suitable TLR-4 ligands capable of triggering a signaling response through TLR-4 include, for example, lipopolymers from Gram-negative bacteria and derivatives thereof, or fragments thereof, especially non-toxic derivatives of LPS (such as MPL). It is saccharide. Other suitable TLR agonists include: heat shock protein (HSP) 10, 60, 65, 70, 75 or 90; Surfactant protein A, hyaluronan oligosaccharide, heparin sulfate fragment, fibronectin fragment, fibrinogen peptide and B-defensin-2, and muramyl dipeptide (MDP). For example, the TLR agonist may be HSP 60, 70 or 90. Other suitable TLR-4 ligands are as described in WO 2003/011223 and WO 2003/099195.

Additional TLR agonists (such as agonists capable of eliciting a signaling response through the TLR signaling pathway) are also useful as adjuvants, such as agonists against TLR2, TLR3, TLR7, TLR8 and/or TLR9. Accordingly, the composition may contain a TLR-1 agonist, a TLR-2 agonist, a TLR-3 agonist, a TLR-4 agonist, a TLR-5 agonist, a TLR-6 agonist, a TLR-7 agonist, a TLR-8 agonist, a TLR-9 agonist, or any of these. It may further include an auxiliary selected from the group consisting of a combination of. For example, TLR-1, including tri-acylated lipopeptides (LPs); phenol-soluble modulin; Mycobacterium tuberculosis LP; S-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmi, mimicking the acetylated amino terminus of bacterial lipoprotein and OspA LP from Borrelia burgdorferi Toyl-(R)-Cys-(S)-Ser-(S)-L-ys(4)-OH, trihydrochloride (Pam3Cys) can trigger signaling reactions through one or more of the following LPs: Any TLR agonist may be used. For example, one or more lipoproteins, peptidoglycans, bacterial lipopeptides from M. tuberculosis, B. burgdorferi or T. pallidum; peptidoglycan from species including Staphylococcus aureus; lipoteichoic acid, mannuronic acid, Neisseria porin, bacterial fimbriae, Yersina virulence factor, CMV virion, measles hemagglutinin TLR agonists that can trigger a signaling response through TLR-2, such as the measles haemagglutinin and zymosan from yeast, can be used. In addition, one or more of the molecular nucleic acid patterns associated with viral infection, double stranded RNA (dsRNA) or polyinosinicpolycytidylic acid (Poly IC), trigger signaling responses through TLR-3. Any TLR agonist that can be used can be used. Additionally, a TLR agonist that can trigger a signal transduction reaction through TLR-5, such as bacterial flagellin, can be used. Additionally, TLR agonists capable of triggering a signaling response through TLR-6, such as one or more mycobacterial lipoproteins, di-acylated LP, and phenol-soluble modulin, can be used. Additional TLR6 agonists are described in WO 2003/043572. For example, one or more of single stranded RNA (ssRNA), loxoribine, guanosine analogues at positions N7 and CS, or imidazoquinoline compounds, or derivatives thereof. TLR agonists that can trigger signaling responses through TLR-7 can be used. In one embodiment, the TLR agonist may be imiquimod. Additional TLR-7 agonists are described in WO 2002/085905. Additionally, TLR agonists that can trigger a signaling response through TLR-8 can be used. Suitably, the TLR agonist capable of triggering a signaling response through TLR-8 is a single-stranded RNA (ssRNA), an imidazoquinoline with antiviral activity, such as resiquimod (R848) molecule; Resiquimod can also be recognized by TLR-7. Other TLR-8 agonists that may be used include those described in WO 2004/071459. Additionally, the adjuvant may include a TLR agonist capable of inducing a signaling response through TLR-9. For example, the adjuvant may include HSP90, bacterial or viral DNA, and/or DNA comprising unmethylated CpG nucleotides (e.g., CpG oligonucleotides). For example, CpG-containing oligonucleotides primarily induce Th1 responses. Such oligonucleotides are well known and are described, for example, in WO 95/26204, WO 96/02555, WO 99/33488 and US Patents 5,278,302, 5,666,153, and 6,008,200 and 5,856,462. Accordingly, oligonucleotides for use as adjuvants in the disclosed compositions include, for example, CpG-containing oligonucleotides comprising two or more dinucleotide CpG motifs. Oligonucleotides with mixed internucleotide linkages are also included.

Adjuvants may also include aluminum or calcium salts, especially mineral salts such as aluminum hydroxide, aluminum phosphate and calcium phosphate.

Combinations of different adjuvants can also be used in the pharmaceutical compositions described herein. For example, as already mentioned, QS21 can be formulated with (3D-)MPL. The ratio of QS21:(3D-)MPL is typically 1:10 to 10:1, such as approximately 1:5 to 5:1; Often it is practically 1:1. Typically, the ratio ranges from 2.5:1 to 1:1 (3D-)MPL:QS21 (eg AS01 (GlaxoSmithKline)). Other combination adjuvant formulations include (3D-)MPL and aluminum salts such as aluminum hydroxide (e.g. AS04 (GlaxoSmithKline)). When formulated in combination, this combination can enhance antigen-specific Th1 immune responses. The adjuvant preparation may contain mineral salts such as calcium salts or aluminum (alum) salts, for example calcium phosphate, aluminum phosphate or aluminum hydroxide. Additionally, adjuvants may include oil and water emulsions, such as oil-in-water emulsions (such as MF59 (Novartis) or AS03 (GlaxoSmithKline)). An example of an oil-in-water emulsion is a metabolizable oil such as squalene, a tocol such as tocopherol, such as alpha-tocopherol, and sorbitan trioleate (Span 85) or Contains surfactants such as polyoxyethylene sorbitan monooleate (Tween 80).

Furthermore, the pharmaceutical compositions according to the invention, in particular vaccines, preferably also comprise additional components such as peptides or proteins which aggregate with the peptides/proteins according to the invention to form particle-like aggregates. An example of such a component is HBsAg or fragments thereof described herein. Accordingly, the HBsAg or fragment thereof described herein may (i) consist of a (fusion) protein according to the invention and/or (ii) be present in a pharmaceutical composition according to the invention (“free” HBsAg), The (fusion) protein can aggregate with “free” HBsAg to form particles.

Medical Treatments, Kits, and Uses

medical treatment

In a further aspect, the present invention provides a pharmaceutical

(i) a peptide according to the invention;

(ii) a protein according to the invention;

(iii) a nucleic acid encoding a protein or peptide according to the invention;

(iv) virus-like particles according to the invention;

(v) protein nanoparticles according to the present invention;

(vi) an antibody according to the invention, or an antibody fragment thereof;

(vii) a nucleic acid encoding an antibody, or antibody fragment according to the invention;

(viii) a vector comprising a nucleic acid according to the invention;

(ix) cells expressing an antibody or peptide according to the invention or containing a vector according to the invention; and/or

(x) Pharmaceutical composition according to the present invention

Provides the purpose of.

preferably

(i) a peptide according to the invention;

(ii) a protein according to the invention;

(iii) a nucleic acid encoding a protein or peptide according to the invention;

(iv) virus-like particles according to the invention;

(v) protein nanoparticles according to the present invention;

(vi) an antibody according to the invention, or an antibody fragment thereof;

(vii) a nucleic acid encoding an antibody, or antibody fragment according to the invention;

(viii) a vector comprising a nucleic acid according to the invention;

(ix) cells expressing an antibody or peptide according to the invention or containing a vector according to the invention; and/or

(x) Pharmaceutical composition according to the present invention

is used to prevent and/or treat malaria.

In other words, the antibody, or antigen-binding fragment thereof according to the present invention is preferably for use in the prevention and/or treatment of malaria. Additionally, the peptide and/or protein according to the present invention is preferably used for the prevention and/or treatment of malaria. Most preferably, the pharmaceutical composition according to the invention as described above is for use in the prevention and/or treatment of malaria.

Preferably, the malaria to be prevented and/or treated is caused by Plasmodium falciparum (infection).

Malaria prophylaxis refers in particular to a prophylactic setting, where the subject has not been diagnosed with malaria (diagnosis was not performed or the diagnosis was negative) and/or the subject has not shown symptoms of malaria. Preferably, the product of the invention is administered prior to Plasmodium falciparum infection, for example. However, malaria prevention also includes “post-exposure prophylaxis” (PEP), i.e. prophylactic treatment after possible Plasmodium falciparum infection, for example after a mosquito bite in a Plasmodium falciparum affected area. Malaria prophylaxis is particularly useful for high-risk subjects, such as subjects staying in malaria-affected areas (such as subjects residing in or traveling to malaria-affected areas).

Therefore, the peptide according to the invention, the protein according to the invention, the virus-like particle according to the invention, the protein nanoparticle according to the invention, the antibody according to the invention, or the antigen-binding fragment thereof, the nucleic acid according to the invention, the invention The vector according to the present invention, the cell according to the present invention or the pharmaceutical composition according to the present invention are preferably used for the prevention of malaria in subjects not diagnosed with malaria or in subjects without malaria symptoms.

In contrast, in a treatment setting, subjects are typically diagnosed with malaria and/or exhibit symptoms of malaria. Note that the terms "treatment" and "therapy"/"therapeutic" of malaria include (complete) cure as well as attenuation of malaria.

Accordingly, the peptide according to the invention, the protein according to the invention, the virus-like particle according to the invention, the protein nanoparticle according to the invention, the antibody according to the invention, or antigen-binding fragment thereof, the nucleic acid according to the invention, the invention The vector according to the present invention, the cell according to the present invention or the pharmaceutical composition according to the present invention are preferably used for the treatment of malaria in subjects diagnosed with malaria or in subjects showing malaria symptoms.

Peptide according to the present invention, protein according to the present invention, virus-like particle according to the present invention, protein nanoparticle according to the present invention, antibody according to the present invention, or antigen-binding fragment thereof, nucleic acid according to the present invention, The vector, the cell according to the invention or the pharmaceutical composition according to the invention are also preferably used for the prevention and/or treatment of malaria in asymptomatic subjects. These subjects may or may not be diagnosed with malaria.

Peptide according to the invention, protein according to the invention, virus-like particle according to the invention, protein nanoparticle according to the invention, antibody according to the invention, or antigen-binding fragment thereof, nucleic acid according to the invention, nucleic acid according to the invention Vectors, cells according to the invention or pharmaceutical compositions according to the invention are used for preventing malaria, and include the peptide according to the invention, the protein according to the invention, the virus-like particle according to the invention, and the protein nanoparticle according to the invention. , an antibody according to the invention, or an antigen-binding fragment thereof, a nucleic acid according to the invention, a vector according to the invention, a cell according to the invention or a pharmaceutical composition according to the invention is (possibly) up to 3 months prior to malaria parasite infection, Preferably (possibly) up to 1 month before malaria parasite infection, more preferably (possible) up to 2 weeks before malaria parasite infection, even more preferably (possible) up to a week before malaria parasite infection, most preferably (possible) It is administered until the day before malaria parasite infection. This treatment schedule refers specifically to the preventive setting.

In general, a peptide according to the invention, a protein according to the invention, a virus-like particle according to the invention, a protein nanoparticle according to the invention, an antibody according to the invention, or an antigen-binding fragment thereof, a nucleic acid according to the invention, The vector according to the invention, the cell according to the invention or the pharmaceutical composition according to the invention may be administered once or repeatedly. Therefore, the peptide according to the invention, the protein according to the invention, the virus-like particle according to the invention, the protein nanoparticle according to the invention, the antibody according to the invention, or the antigen-binding fragment thereof, the nucleic acid according to the invention, the invention After the first administration of the vector according to the invention, the cell according to the invention or the pharmaceutical composition according to the invention, one or more subsequent administrations are preferably carried out in 1, 2, 3, 4, 5, 6, 7, 8, 9 , may be administered as a single dose once daily or once every two days for 10, 11, 12, 13, 1, 15, 16, 17, 18, 19, 20, or 21 days. In addition, the peptide according to the present invention, the protein according to the present invention, the virus-like particle according to the present invention, the protein nanoparticle according to the present invention, the antibody according to the present invention, or the antigen-binding fragment thereof, the nucleic acid according to the present invention, the present invention After the first administration of the vector according to the invention, the cell according to the invention or the pharmaceutical composition according to the invention, one or more subsequent administrations are preferably carried out in 1, 2, 3, 4, 5, 6, 7, 8, 9 , preferably administered as a single dose once or twice per week for 10, 11, 12, 13, 1, 15, 16, 17, 18, 19, 20 or 21 weeks. In addition, the peptide according to the present invention, the protein according to the present invention, the virus-like particle according to the present invention, the protein nanoparticle according to the present invention, the antibody according to the present invention, or the antigen-binding fragment thereof, the nucleic acid according to the present invention, the present invention After the first administration of the vector according to the invention, the cell according to the invention or the pharmaceutical composition according to the invention, one or more subsequent administrations are preferably carried out in 1, 2, 3, 4, 5, 6, 7, 8, 9 , preferably administered as a single dose once every two or four weeks for 10, 11, 12, 13, 1, 15, 16, 17, 18, 19, 20 or 21 weeks. In addition, the peptide according to the present invention, the protein according to the present invention, the virus-like particle according to the present invention, the protein nanoparticle according to the present invention, the antibody according to the present invention, or the antigen-binding fragment thereof, the nucleic acid according to the present invention, the present invention After the first administration of the vector according to the invention, the cell according to the invention or the pharmaceutical composition according to the invention, one or more subsequent administrations are preferably carried out in 1, 2, 3, 4, 5, 6, 7, 8, 9 , preferably administered once every two or four months as a single dose for 10, 11, 12, 13, 1, 15, 16, 17, 18, 19, 20 or 21 months. In addition, the peptide according to the present invention, the protein according to the present invention, the virus-like particle according to the present invention, the protein nanoparticle according to the present invention, the antibody according to the present invention, or the antigen-binding fragment thereof, the nucleic acid according to the present invention, the present invention After the first administration of the vector according to the invention, the cell according to the invention or the pharmaceutical composition according to the invention, one or more subsequent administrations are preferably carried out in 1, 2, 3, 4, 5, 6, 7, 8, 9 Alternatively, it is preferable that it can be administered as a single dose once or twice a year for 10 years.

Preferably, a peptide according to the invention, a protein according to the invention, a virus-like particle according to the invention, a protein nanoparticle according to the invention, an antibody according to the invention, or an antigen-binding fragment thereof, a nucleic acid according to the invention, The vector according to the invention, the cell according to the invention or the pharmaceutical composition according to the invention is administered in a (single) dose of 0.005 to 100 mg/kg body weight, preferably a (single) dose of 0.0075 to 50 mg/kg body weight, more Preferably in a (single) dose of 0.01 to 10 mg/kg of body weight, even more preferably in a (single) dose of 0.05 to 5 mg/kg of body weight, and particularly preferably in a (single) dose of 0.1 to 1 mg/kg of body weight. is administered.

Peptide according to the invention, protein according to the invention, virus-like particle according to the invention, protein nanoparticle according to the invention, antibody according to the invention, or antigen-binding fragment thereof, nucleic acid according to the invention, nucleic acid according to the invention Vectors, cells according to the invention or pharmaceutical compositions according to the invention may be administered orally, intravenously, intramuscularly, intraarterially, intramedullary, intraperitoneally, intrathecally, intraventricularly, transdermal, transcutaneous, topically. , can be administered by any number of routes, such as subcutaneous, intranasal, enteral, sublingual, intravaginal, or rectal routes. Intravenous administration, subcutaneous administration, or intramuscular administration is preferred, and intravenous administration or subcutaneous administration is more preferred.

Accordingly, the present invention also provides a method for preventing and/or treating malaria in a subject, which method provides a method for preventing and/or treating malaria in a subject in need thereof.

i) a peptide according to the invention;

(ii) a protein according to the invention;

(iii) a nucleic acid encoding a protein or peptide according to the invention;

(iv) virus-like particles according to the invention;

(v) protein nanoparticles according to the present invention;

(vi) an antibody according to the invention, or an antibody fragment thereof;

(vii) a nucleic acid encoding an antibody, or antibody fragment according to the invention;

(viii) a vector comprising a nucleic acid according to the invention;

(ix) cells expressing an antibody or peptide according to the invention or containing a vector according to the invention; and/or

(x) Pharmaceutical composition according to the present invention

It includes administering.

Preferred embodiments of this method correspond to preferred embodiments of medical use as described above.

Additional uses and kits

In a further aspect, the present invention also provides an antibody, or antibody fragment thereof, or the present invention for monitoring the quality of an anti-malarial vaccine by checking whether the antigen of the vaccine contains a specific epitope in the correct form. It provides a use of the pharmaceutical composition according to. Preferred antigens of which such anti-malarial vaccines are comprised include peptides according to the invention as described above.

In addition, the present invention is also used in the diagnosis of malaria infection.

(i) a peptide according to the invention;

(ii) a protein according to the invention;

(iii) a nucleic acid encoding a protein or peptide according to the invention;

(iv) virus-like particles according to the invention;

(v) protein nanoparticles according to the present invention;

(vi) an antibody according to the invention, or an antibody fragment thereof;

(vii) a nucleic acid encoding an antibody, or antibody fragment according to the invention;

(viii) a vector comprising a nucleic acid according to the invention;

(ix) cells expressing an antibody or peptide according to the invention or containing a vector according to the invention; and/or

(x) Pharmaceutical composition according to the present invention

Provides the purpose of.

Additionally, isolated blood samples (e.g., whole blood, serum, and/or plasma) may be used to determine whether the malaria parasite is infected.

(i) a peptide according to the invention;

(ii) a protein according to the invention;

(iii) a nucleic acid encoding a protein or peptide according to the invention;

(iv) virus-like particles according to the invention;

(v) protein nanoparticles according to the present invention;

(vi) an antibody according to the invention, or an antibody fragment thereof;

(vii) a nucleic acid encoding an antibody, or antibody fragment according to the invention;

(viii) a vector comprising a nucleic acid according to the invention;

(ix) cells expressing an antibody or peptide according to the invention or containing a vector according to the invention; and/or

(x) Pharmaceutical composition according to the present invention

The purpose of is provided.

The diagnostic method may include contacting the sample with an antibody or peptide/protein according to the invention. These samples may be from a subject, such as the nasal cavity, sinus cavity, salivary glands, lungs, liver, pancreas, kidneys, ears, eyes, placenta, digestive tract, heart, ovaries, pituitary gland, adrenal glands, thyroid gland, brain, skin or blood, Preferably, it may be isolated from the subject, such as an isolated tissue sample taken from plasma or serum. The diagnostic method may also include the detection of antigen/antibody complexes, especially after contacting the sample with an antibody or peptide/protein according to the invention. This detection step is typically performed on the bench, i.e. without contact with human or animal bodies. Examples of detection methods are well known to those skilled in the art and include, for example, ELISA (enzyme-linked immunosorbent assay).

In a further aspect, the invention also provides at least one peptide according to the invention, at least one protein according to the invention, at least one virus-like particle according to the invention, at least one protein nanoparticle according to the invention, at least One pharmaceutical composition according to the invention, at least one antibody according to the invention, or antigen-binding fragment thereof, at least one nucleic acid according to the invention, at least one vector according to the invention, at least one antibody according to the invention A kit of parts comprising cells and/or at least one pharmaceutical composition according to the invention is provided. Furthermore, the kit may contain a peptide according to the invention, a protein according to the invention, a nucleic acid encoding a protein or peptide according to the invention, a virus-like particle according to the invention, a protein nanoparticle according to the invention, an antibody according to the invention, or an antibody fragment thereof, an antibody according to the invention, or a nucleic acid encoding an antibody fragment, a vector comprising a nucleic acid according to the invention, a cell expressing an antibody or peptide according to the invention or comprising a vector according to the invention, and /or instructions for administration of a pharmaceutical composition according to the invention and/or a peptide according to the invention, a protein according to the invention, a nucleic acid encoding a protein or peptide according to the invention, a virus-like particle according to the invention, the present invention Protein nanoparticles according to the invention, antibodies according to the invention, or antibody fragments thereof, nucleic acids encoding antibodies according to the invention, or antibody fragments, vectors containing nucleic acids according to the invention, antibodies or peptides according to the invention It may contain a booklet together with means such as a syringe or vessel for the administration of cells expressing or containing a vector according to the invention, and/or a pharmaceutical composition according to the invention.

The novel malaria vaccine and antibody that binds to Plasmodium falciparum spores of the present invention specifically binds to Plasmodium falciparum spores and can be used for the treatment and/or prevention of malaria.

A brief description of the accompanying drawings will be provided below. The drawings are intended to explain the present invention in more detail. However, it is not intended to limit the patentable subject matter of the present invention in any way.
Figure 1 shows the monoclonal antibodies MGG1, MGG2, MGG3, MGG4 and MGG8 for Example 1 (each based on the VH/VL genes of the antibody isolated from Donor G) and the control antibody BKC3 against P. falciparum. Exemplary staining of protozoan sporozoites is shown. Sporozoites were labeled with SYBR Green I and incubated with monoclonal antibodies. Antibody detection was performed with anti-human IgG coupled to a fluorophore.
Figure 2 shows for Example 2: (A) a schematic overview of the assays used and (B) lysis of hepatocytes by human monoclonal antibodies MGG1, MGG2, MGG3, MGG4, MGG8, MGH1, MGH2, MGH3 and control antibody 2A10. It shows inhibition of sporozoite traversal and invasion (ISTI).
Figure 3 shows for Example 2 (A) a schematic overview of the experimental design of an in vivo humanized mouse model of sporozoite infestation and (B) in vivo reduction of sporozoites by selected antibodies MGG4, MGG8, MGH1, MGH2 and MGH3. .
Figure 4 shows (A) Schematic overview of Plasmodium falciparum circosporozoite proteins for Example 3. SP is signal peptide; RI is area I. (B) Sequence of PfCSP (NF54, Uniprot accession number P19597; SEQ ID NO: 24 isolate). Functionally important region I is shown in bold. (C) Sequences of CSP peptides tested for binding by antibodies: 22-110-peptide (SEQ ID NO: 27), NPDP-peptide (SEQ ID NO: 23), and NANP-peptide (SEQ ID NO: 26). Amino acids belonging to region I are shown in bold.
Figure 5 shows the binding of monoclonal antibodies to different peptides by ELISA for Example 3. Different dilutions of antibodies were tested for binding to CSP peptides (sequences are shown in Figure 4) and EC50 values were calculated for each antibody. Antibodies tested in in vivo mouse models are boxed. The two antibodies that showed the best protection in this model (MGG4 and MGH2) showed good binding to the NPDP peptide and VH3-30 was used. All other antibodies that bound strongly to NPDP (with EC50 <100 ng/ml) also used VH3-30. One antibody, MGV3, bound relatively weakly to NPDP and 22-110 but did not bind to the NANP repeat region.
Figure 6 shows the binding of monoclonal antibodies MGV3, MGG4, MGU5 and MGG1 to overlapping peptides from CSP for Example 4. Only the CSP region showing binding by monoclonal antibodies is shown.
Figure 7 shows inhibition of binding of MGV3 by different monoclonal antibodies for Example 5. Binding inhibition was calculated by the median fluorescence intensity (FI) of IgG binding to sporozoites. MGU3 is an antibody that binds to the C-terminus of CSP, MGV3 binds to the NPDP region of the N-terminus, and the remaining antibodies bind to the repeat region of CSP.
Figure 8 shows identification of antibodies that bind to the C-terminal binding site in CSP for Example 6. Briefly, C-terminal peptide 282-383 was coated at a concentration of 1 μg/ml, and B cell supernatants were tested from 1/3 dilution to 1/648 dilution. MGU3 is given as an example of an antibody that can bind peptides, whereas MGU1, MGU5 and MGU8 cannot bind peptides.

Below, specific examples are presented that illustrate various embodiments and aspects of the invention. However, the present invention should not be limited in scope by the specific embodiments described herein. The following preparations and examples are provided to enable those skilled in the art to more clearly understand and practice the present invention. However, the present invention is not limited in scope by the illustrated embodiments, which are intended as illustrations of a single aspect of the present invention, and functionally equivalent methods are within the scope of the present invention. Indeed, various modifications of the present invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description, accompanying drawings and examples below. All such modifications are within the scope of the appended claims.

Example 1: Isolation of human monoclonal antibodies that bind to Plasmodium falciparum sporozoites

Four Tanzanian donors (identified as donors G, H, U and V) protected from malaria challenge were selected for isolation of human monoclonal antibodies. For this purpose, peripheral blood mononuclear cells (PBMCs) were isolated from blood samples of four donors. IgG memory B cells were isolated from frozen peripheral blood mononuclear cells (PBMCs) by magnetic cell sorting. B cells were incubated with 0.5 μg/ml anti-CD19-PECy7 antibody for 20 minutes on ice and then with mouse anti-PE microbeads for 30 minutes on ice. Cells were then stained with 3.75 μg/ml goat Alexa Fluor 647-conjugated anti-human IgG for 20 minutes on ice and sorted by FACS. Traggiai et al. (2004) Nat Med. As previously described in 10, 871-875, sorted B cells were immortalized with Epstein-Barr virus (EBV) and single-cell cultured in the presence of CpG and irradiated PBMC-feeder cells. Plated in water. After 14 days, culture supernatants were screened using a high-throughput flow cytometer for their ability to stain sporozoites. In this assay, sporozoites were labeled with 6.25x SYBR Green I and incubated with B cell culture supernatant at ½ dilution for 30 min at room temperature. Without any washing steps, sporozoites were incubated with 1 μg/ml goat Alexa Fluor 647-conjugated anti-human IgG for 1 hour at 4°C and analyzed by flow cytometry.

For sporozoite staining using recombinant monoclonal antibodies, sporozoites were stained with 6.25x SYBR Green I and incubated with monoclonal antibodies for 30 min at room temperature. The sporozoites were then washed once and stained with 2.5 μg/ml goat Alexa Fluor 647-conjugated anti-human IgG for 30 min at room temperature and analyzed by flow cytometry.

An example of sporozoite staining is shown in Figure 1. Figure 1 shows exemplary staining of Plasmodium falciparum sporozoites with monoclonal antibodies MGG1, MGG2, MGG3, MGG4 and MGG5 (each based on the VH/VL genes of antibodies isolated from donor G) and negative control antibodies.

Positive cultures were expanded and VH and VL genes from individual clones were sequenced and cloned into human IgG1, Igκ, and Igλ expression vectors (kindly provided by Michel Nussenzweig, Rockefeller University, New York, US) essentially as described. (Tiller T, Meffre E, Yurasov S, Tsuiji M, Nussenzweig MC, Wardemann H (2008) Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 329: 112-124 ) Expression was achieved by transient transfection of Expi293F cells using polyethylenimine (PEI).

Table 5 below shows exemplary human monoclonal antibodies found to bind to Plasmodium falciparum sporozoites with the use of VH and VL (see Tables 1 and 2 for sequence numbers): Heavy chain Light chain VH J.H. V.L. J.L. Donor G MGG1 VH3-20 JH6 VL1-51 JL3 MGG2 VH3-74 JH5 VL7-46 JL2/JL3 MGG3 VH3-30 JH2 VK2-29 JK1 MGG4 VH3-30 JH3 VK4-1 JK4 MGG8 VH3-73 JH5 VK2D-29 JK1 Donor H MGH1 VH1-2 JH4 VK2-30 JK2 MGH2 VH3-30 JH4 VK2-30 JK1 MGH3 VH3-21 JH4 VK1-47 JK3 Donor U MGU1 VH3-30 JH3 VL4-69 JL3 MGU3 VH3-48 JH4 VK1-33 JK4 MGU5 VH3-30 JH3 VK1-33 JK4 MGU8 VH3-30 JH3 VK1-33 JK1/JK4 MGU10 VH3-30 JH3 VL4-69 JL3 MGU11 VH3-33 JH3 VK2-30 JK3 MGU12 VH3-30 JH3 VK1-5 JK1 Donor V MGV3 VH3-66 JH6 VK3-20 JK2

Example 2: Several monoclonal antibodies show potent anti-sporadic function in vitro and in vivo

During the hepatic stage of the malaria parasite life cycle, sporozoites often pass through hepatocytes before productive invasion of target hepatocytes. Exemplary monoclonal antibodies MGG1, MGG2, MGG3, MGG4, MGG8, MGH1, MGH2 and MGH3 (see Tables 1 and 2 for sequence numbers) were tested in vitro for their ability to inhibit sporozoite passage and invasion of hepatocytes. . For this purpose, a quantitative flow cytometry-based assay was used, as described in Kaushansky A, Rezakhani N, Mann H, Kappe SH, 2012: Development of a quantitative flow cytometry-based assay to assess infection by Plasmodium falciparum sporozoites . Mol Biochem Parasitol. Described in 183(1):100-3. A schematic overview of this analysis is shown in Figure 2A. Briefly, in this assay, the hepatocyte HC04 cell line was infected with Plasmodium falciparum sporozoites in the presence of FITC-dextran. Sporozoite passage was measured by uptake of FITC-dextran, which can enter hepatocytes with damaged membranes during passage. Sporozoite invasion was measured by staining sporozoites in hepatocytes with anti-circumsporozoite protein (anti-CSP) antibody. As a control, the murine monoclonal antibody 2A10 targeting the NANP repeat region of the circumsporozoite protein (Zavala F. et al ., 1983, J. Exp. Med. 157: 1947 - 1957; Wirtz RA et al . al ., 1987, Bulletin of the World Health Organization 65(1): 39 - 45) was used.

The results are shown in Figure 2B. Here, the percentage of sporozoite invasion or crossing is measured in the presence of the monoclonal antibody of interest compared to when an irrelevant IgG is added. A low percentage indicates good inhibition by the monoclonal antibody. In this assay, MGG4, MGH1, MGH2 and MGH3 showed the highest inhibition of sporozoite invasion. Therefore, these antibodies were selected for further testing together with MGG8.

The selected monoclonal antibodies were essentially Sack et al. (Sack et al., 2014, Infection and Immunity 82(2): 808-817. Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum) and especially Vaughan et al. (Vaughan et al., 2012, J Clin Invest 122 , 3618-3628. The FRG huHEP liver-chimeric mouse model measures sporozoite invasion and liver-stage parasite multiplication in mice with humanized livers) As described, FRG was tested in the huHEP liver-chimeric mouse model. A schematic outline of the experimental design is shown in Figure 3A. In this model, antibodies are first injected into mice, which are then infected 16-24 hours later with Plasmodium falciparum sporozoites from mosquito bites. Liver parasite burden was detected by imaging 6 days after infection.

The results are shown in Figure 3B. Liver burden in mice injected with the monoclonal antibody of interest was measured and calculated as a percentage of the liver burden in mice injected with non-specific IgG. The greatest reduction in liver burden was observed in mice injected with antibodies MGG4 or MGH2 (only 2.5% and 5.5% liver burden, respectively, compared to negative control mice).

Example 3: A potent monoclonal antibody exhibits a unique binding pattern to CSP and uses VH3-30

Malaria parasite circosporozoite protein (CSP) is an immunodominant protein that coats the entire sporozoite surface and plays an important role in sporozoite function. As shown in Figure 4A, this protein contains an N-terminal portion that begins with the signal peptide (SP) and ends with region I (RI). Region I is a pentapeptide (KLKQP; SEQ ID NO: 25) that is involved in binding to hepatocytes and mosquito salivary glands. In CSP, region I is followed by a C-terminal thrombospondin-like domain containing a T cell epitope and a NANP repeat region, which is the immunodominant site for antibodies (Figure 4A). Figure 4B shows an exemplary sequence of the circosporozoite protein of Plasmodium falciparum isolate NF54 (SEQ ID NO: 24).

An antigen-agnostic approach as described in Example 1 was used to identify any antibodies that could bind to the sporozoite surface. In this approach, all antibodies shown in Table 5 were found to bind to CSP, confirming the immunodominance of this protein (data not shown).

Next, we tested the binding of antibodies to peptides from different parts of the CSP, as shown in Figure 4C. In this assay, half-area 96-well ELISA plates were incubated with total recombinant CSP (SEQ ID NO: 24; 1 μg/ml), NANP-peptide (SEQ ID NO: 26; 2 μg/ml) overnight at 4°C. ), NPDP-peptide (SEQ ID NO: 23; 5 μg/ml) or 22-110-peptide (SEQ ID NO: 27; 1 μg/ml). Plates were blocked with 1% bovine serum albumin in PBS and incubated with titrated antibodies followed by AP-conjugated goat anti-human IgG. The plate was then washed, substrate (p-NPP) was added and the plate was read at 405 nm.

Results are shown in Figure 5 with antibodies tested in the in vivo mouse model shown in the box. Interestingly, of the five antibodies tested in the in vivo assay (MGG4, MGG8, MGH1, MGH2, MGH3), the two antibodies that showed the best function in the in vivo assay (MGG4, MGH2, see Example 2) were directed against the NPDP-peptide. (SEQ ID NO: 23), that is, it is well bound to the CSP of the junction between the N-terminus and the NANP repeat region. The other three antibodies tested in the in vivo assay (MGG8, MGH1, MGH3) showed poor or negligible binding to this region. In contrast, binding affinity for peptides containing only repeat regions or the entire CSP did not distinguish antibodies with different functional abilities in in vivo assays.

Interestingly, the CSP region to which the most potent antibodies MGG4 and MGH2 bind, i.e. the junction between the N-terminus and the NANP repeat region, is not included in the major malaria vaccine RTS,S. Rather, RTS,S integrates the C-terminal half and C-terminal domain of the NANP repeat region. Our data suggest that the junction between the N-terminus and the NANP repeat region is an important target for antibodies from protected individuals, showing the strongest functionality in in vivo models. Without being bound by any theory, we believe that this region may be important due to its proximity to region I, which is thought to be the target of the parasite protease that cleaves the N-terminus of CSP during hepatocyte invasion (Coppi et al. (2011) J Exp Med 208, 341-356; Coppi et al. (2005) J Exp Med 201, 27-33).

Additional antibodies that bound well to the NPDP-peptide (SEQ ID NO: 23) include MGG3, MGU5, MGU8 and MGU12.

Additionally, all antibodies that bound well to NPDP-peptides (MGG4, MGH2, MGG3, MGU5, MGU8 and MGU12) used VH3-3, suggesting that the use of this VH is preferential for binding to this core region.

One antibody, MGV3, was found to bind relatively weakly to NPDP-peptide and 22-110-peptide but not to NANP-peptide. This indicates that antibody MGV3 recognizes the N-terminus of the CSP and NPDP-domains but not the NANP repeat region. Therefore, MGV3 appears to bind slightly to the N-terminus compared to the binding sites of MGG4, MGH2, MGG3, MGU5, MGU8 and MGU12.

Other antibodies were found to bind weakly to NPDP-peptide and 22-110-peptide, showing a binding site in (middle) of the NANP-repeat region, although they bound well to NANP-peptide. These antibodies include MGU11, MGU1, MGH3, MGH1, MGG8 and to a lesser extent MGG2 and MGG1.

Only antibody MGU3 showed binding to total PfCSP, but did not bind to any of the CSP-peptides used (22-110, NPDP-peptide, NANP-peptide). This may represent a binding site for MGU3 located at the C-terminus of the NANP-repeat in CSP.

Example 4: Fine epitope mapping of monoclonal antibodies

To identify the exact region of CSP targeted by the monoclonal antibody, linear epitope mapping of selected antibodies was performed against CSP (PEPperMAP® by PEPperPRINT GmbH, Heidelberg, Germany). To this end, antibodies MGV3, MGG4, MGU5 and MGG1 were tested for binding to an array of 15-aa CSP peptides (moved by a single amino acid) covering the entire protein (Figure 6). In summary, the sequence of circosporozoite protein (CSP) was extended by a neutral GSGSGSG linker (SEQ ID NO: 28) at the C- and N-terminus to avoid truncated peptides. The extended antigen sequence was translated into a linear 15 amino acid peptide with a peptide-peptide overlap of 14 amino acids (Figure 6). The resulting CSP peptide microarray consists of 457 different peptides (914 peptide spots) printed in duplicate, an additional custom control peptide (2 spots of each control), a c-Myc control (2 spots), and an in-frame frame of the HA control peptide. (82 spots) were included. CSP peptide microarrays were incubated with antibody samples at concentrations of 1 μg/ml, 10 μg/ml, and 100 μg/ml in incubation buffer, then stained with secondary and control antibodies, and analyzed using the LI-COR Odyssey Imaging System (LI-COR Odyssey Imaging System). Quantification of spot intensity and peptide annotation was performed with a PepSlide® analyzer.

The results are shown in Figure 6. MGV3, a peptide that does not recognize the NANP repeat region but recognizes the N-terminus and the NPDP peptide (Figure 5), appears to bind to the NPDP motif, whereas MGG4 and MGU5 can bind to the first NANP repeat proximal to this region. It turned out that

Example 5: Inhibition of binding of MGV3 to intact sporozoites

Next, we tested whether monoclonal antibodies MGG1, MGG4, MGU5, and MGU3 could inhibit the binding of MGV3 to sporozoites in a blocking-of-binding (BOB) assay. In this assay, sporozoites were stained with 3.3x SYBR Green I and incubated with titrated monoclonal antibodies (0.1 to 100 μg/ml) for 20 minutes at room temperature. Without washing, sporozoites were then incubated with 10 μg/ml of biotin-labeled MGV3 for 20 min at room temperature. Sporozoites were washed twice, incubated with streptavidin conjugated to Alexa Fluor 647 for 20 minutes at room temperature, and analyzed by flow cytometry. The degree of inhibition of biotinylated MGV3 binding was measured using the decrease in median fluorescence intensity (median FI) in the Alexa Fluor 647 channel.

The results are shown in Figure 7. MGG4 and MGU5, which bind well to the NPDP peptide and can bind to the first NANP repeat based on the peptide alignment results (Figure 6), can inhibit binding by MGV3, whereas MGG1, which is located further away from the N-terminus, can inhibit binding by MGV3. Binding cannot be effectively inhibited. This confirms the results of Examples 3 and 4 that antibodies that bind NDPD-peptides such as MGG4 and MGU5 bind more of the N-terminal region of CSP than those antibodies that do not bind NDPD-peptides such as MGG1 or MGU3. . In summary, the data suggest that antibodies that bind to NDPD-peptides such as MGG4 and MGU5 have potent functional activity due to their ability to bind closer to the N-terminus.

Of note, unlabeled MGV3 was unable to inhibit binding because overall this antibody binds with low affinity to sporozoites and the concentration of biotinylated MGV3 used was well below the saturation point.

Example 6: Identification of antibodies binding to the C-terminal binding site in CSP

Since the data in Example 3 (Figure 5) suggest that of all the antibodies tested, only antibody MGU3 binds to the C-terminal binding site of CSP, different antibodies were tested for their ability to bind to the C-terminus of CSP.

For this purpose, experiments essentially identical to those described in Example 3 were performed using the antibodies shown in Table 1. However, instead of the CSP-test-peptide (i.e., 22-110-peptide, NPDP-peptide, NANP-peptide) described in Example 3, the C-terminal peptide 282-383 (SEQ ID NO: 312) was used. Briefly, C-terminal peptide 282-383 was coated at a concentration of 1 μg/ml and B cell supernatants were tested from 1/3 dilution to 1/648 dilution.

Results for selected antibodies MGU1, MGU3, MGU5 and MGU8 are shown in Figure 8 (data for other antibodies in Table 1 not shown). As expected from the results of Examples 3 and 5, only antibody MGU3 bound to the C-terminal peptide 282-383, whereas all other antibodies tested did not bind to the C-terminus of CSP. These results confirm that antibody MGU3 binds to the C-terminus of CSP, whereas other antibodies do not bind to that region of CSP.

SEQUENCE TABLE AND SEQUENCE NUMBER (SEQUENCE LISTING): sequence number order note SEQ ID NO: 1 NPDP CSP epitope SEQ ID NO: 2 NPDPN CSP epitope SEQ ID NO: 3 NPDPNA CSP epitope SEQ ID NO: 4 NPDPNAN CSP epitope SEQ ID NO: 5 NPDPNANP CSP epitope SEQ ID NO: 6 NPDPNANPN CSP epitope SEQ ID NO: 7 GNPDPNANP CSP epitope SEQ ID NO: 8 GNDPPNANPN CSP epitope SEQ ID NO: 9 DGNPDPNANP CSP epitope SEQ ID NO: 10 NPDPNANPNK CSP epitope SEQ ID NO: 11 DGNPDPNANPN CSP epitope SEQ ID NO: 12 GNPDPNANPNK CSP epitope SEQ ID NO: 13 DGNPDPNANPNK CSP epitope SEQ ID NO: 14 ADGNPDPNANPN CSP epitope SEQ ID NO: 15 QPADGNPDPNANPNK CSP epitope SEQ ID NO: 16 ADGNPDPNANPNK CSP epitope SEQ ID NO: 17 PADGNPDPNANPNK CSP epitope SEQ ID NO: 18 ADGNPDPNANPNKN CSP epitope SEQ ID NO: 19 PADGNPDPNANPNKN CSP epitope SEQ ID NO: 20 QPADGNPDPNANPNKN CSP epitope SEQ ID NO: 21 PADGNPDPNANPNKNN CSP epitope SEQ ID NO: 22 QPADGNPDPNANPNKNN CSP epitope SEQ ID NO: 23 KQPADGNPDPNANPNKNN NPDP-peptide SEQ ID NO: 24 MMRKLAILSVSSFLFVEALFQEYQCYGSSSNTRVLNELNYDNAGTNLYNELEMNYYGKQENWYSLKKNSRSLGENDDGNNEDNEKLRKPKHKKLKQPADGNPDPNANPNVDPNANPNVDPNANPNVDPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANP NANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNANPNKNNQGNGQGHNMPNDPNRNVDENANANSAVKNNNNEEPSDKHIKEYLNKIQNSLSTEWSPCSVTCGNGIQVRIKPGSANKPKDELDYANDIEKKICKMEKCSSVFNVVNSSIGLIMVLSFLFLN PfCSP SEQ ID NO: 25 KLKQP CSP Area I SEQ ID NO: 26 NANPNANPNANPNANPNANPNANPNANPNANPNANPNANP NANP-peptide SEQ ID NO: 27 EYQCYGSSSNTRVLNELNYDNAGTNLYNELEMNYYGKQENWYSLKKNSRSLGENDDGNNEDNEKLRKPKHKKLKQPADGNPDPNANPNV 22-110-peptide MGG1 SEQ ID NO: 28 GFFDDYA CDRH1 aa SEQ ID NO: 29 INWNGGST CDRH2 aa SEQ ID NO: 30 ARLGRAAREYYYYMDV CDRH3 aa SEQ ID NO: 31 SSNIGNNY CDRL1 aa SEQ ID NO: 32 DNN CDRL2 aa SEQ ID NO: 33 LIY DNN KRP CDRL2 long aa SEQ ID NO: 34 GTWDSSLSAGV CDRL3 aa SEQ ID NO: 35 EVQLVESGGGVVRPGGSLRLSCAAS GFTFDDYA MSWVRQAPGKGLEWVSG INWNGGST GYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYHC ARLGRAAREYYYYYMDV WGKGTTVTVSS VH aa SEQ ID NO: 36 QSVLTQPPSVSAAPGQKVTISCSGS SSNIGNNY VSWYQQLPGTAPKLLIY DNN KRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYC GTWDSSLSAGV FGGGTKLTVLGQ VL aa SEQ ID NO: 37 ggattcacctttgatgattatgcc CDRH1 nuc SEQ ID NO: 38 attaattggaatggtggtagcaca CDRH2 nuc SEQ ID NO: 39 gcgagacttgggagagcagcccgtgagtactactactactactacatggacgtc CDRH3 nuc SEQ ID NO: 40 agctccaaacattgggaataattat CDRL1 nuc SEQ ID NO: 41 gacaataat CDRL2 nuc SEQ ID NO: 42 ctcatttat gacaataat aagcgaccc CDRL2 long nuc SEQ ID NO: 43 ggcacatgggatagcagcctgagtgctggagtg CDRL3 nuc SEQ ID NO: 44 gaggtgcagctggtggagtctgggggaggtgtggtacggcctggggggtccctgagactctcctgtgcagcctct ggattcacctttgatgattatgcc atgagctgggtccgccaagctccagggaaggggctggagtgggtctctggt attaattggaatggtggtagcaca ggttatgcagactctgtgaagggccgattcacca tctccagagacaacgccaagaactccctgtatctgcaaatgaacagtctgagagccgaggacacggccttgtatcactgt gcgagacttgggagagcagcccgtgagtactactactactacatggacgtc tggggcaaagggaccacggtcaccgtctcctca VH nuc SEQ ID NO: 45 cagtctgtgttgacgcagccgccctcagtgtctgcggccccaggacagaaggtcaccatctcctgctctggaagc agctccaacattgggaataattat gtatcctggtaccagcagctcccaggaacagcccccaaactcctcatttat gacaataat aagcgaccctcagggattcctgaccgattctctggctccaagtctggcac gtcagccaccctgggcatcaccggactccagactggggacgaggccgattattactgc ggcacatgggatagcagcctgagtgctggagtg ttcggcggagggaccaagctgaccgtcctaggtcag VL nuc MGG2 SEQ ID NO: 46 GFTLNYW CDRH1 aa SEQ ID NO: 47 INIDGSTT CDRH2 aa SEQ ID NO: 48 AKGSIKAGGFWSGYSNWFDP CDRH3 aa SEQ ID NO: 49 PGPVTSGHY CDRL1 aa SEQ ID NO: 50 DTS CDRL2 aa SEQ ID NO: 51 LIY DTS NKH CDRL2 long aa SEQ ID NO: 52 LLSYGGAPV CDRL3 aa SEQ ID NO: 53 EVQLVESGGGLVQPGGSLRLSCAAS GFTLNNYW MHWVRQAPGKGLVWVAH INIDGSTT TYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYC AKGSIKAGGFWSGYSNWFDP WGQGTLVTVSS VH aa SEQ ID NO: 54 QAVVTQEPSLTVSPGGTVTLTCDSD PGPVTSGHY PYWFQQKPGQVPRTLIY DTS NKHSWTPARFSGSLLGGKAALTLSGAQPEDEADYYC LLSYGGAPV FGGGTKLTVL VL aa SEQ ID NO: 55 ggattcaccctcaataactactgg CDRH1 nuc SEQ ID NO: 56 attaatatcgatggcagtactaca CDRH2 nuc SEQ ID NO: 57 gcaaagggaagtattaaggccggaggtttttggagtggttactccaactggttcgacccc CDRH3 nuc SEQ ID NO: 58 cctggacctgtcaccagtggtcattat CDRL1 nuc SEQ ID NO: 59 gataccagc CDRL2 nuc SEQ ID NO: 60 ctgatttat gataccagc aacaaacac CDRL2 long nuc SEQ ID NO: 61 ctgctctcgtatggtggtgcccctgta CDRL3 nuc SEQ ID NO: 62 gaggtgcagctggtggagtccgggggaggcttagttcagccggggggggtccctgagactctcctgtgcagcctct ggattcaccctcaataactactgg atgcactgggtccgccaagctccagggaaggggctggtctgggtcgcacat attaatatcgatggcagtactaca acctacgcggactccgtgaagggccgattcaccatctcc agagacaacgccaagaacacgctgtatctgcaaatgaacagtctgagagccgaggacacggctgtctattactgt gcaaagggaagtattaaggccggaggtttttggagtggttactccaactggttcgacccc tggggccagggaaccctggtcaccgtctcctcag VH nuc SEQ ID NO: 63 caggctgtggtgactcaggagccctcactgactgtgtccccaggagggacagtcactctcacctgtgactccgac cctggacctgtcaccagtggtcattat ccctactggttccagcagaagcctggccaagtccccaggacactgatttat gataccagc aacaaacactcctggacacctgcccggttttcaggctccctccttg ggggcaaagctgccctgaccctttcgggtgcgcagcctgaggatgaggctgactattactgc ctgctctcgtatggtggtgcccctgta ttcggcggagggaccaaactgaccgtcctaa VL nuc MGG3 SEQ ID NO: 64 GFFTFSTFG CDRH1 aa SEQ ID NO: 65 IWYDGSSK CDRH2 aa SEQ ID NO: 66 VKVGANWGWRYFDL CDRH3 aa SEQ ID NO: 67 QSLLHSDGNTY CDRL1 aa SEQ ID NO: 68 EVS CDRL2 aa SEQ ID NO: 69 LIY EVS SRF CDRL2 long aa SEQ ID NO: 70 MQGIHSWT CDRL3 aa SEQ ID NO: 71 QEQLVESGGGVVQPGKSLRLSCAAS GFTFSTFG MHWVRQAPGKGLEWVAV IWYDGSSK YHADSVKGRFTISRDNSKSTLYLQMNSLRAEDTAMYYC VKVGANWGWRYFDL WGRGTLVTVSS VH aa SEQ ID NO: 72 DIVMTQTPLSLSVTPGQPASISCKSS QSLLHSDGNTY LSWYLQKPGQSPQLLIY EVS SRFSGVPDRFSGSGSGTDFTLKISRVEADDVGVYYC MQGIHSWT FGQGTKVEIK VL aa SEQ ID NO: 73 gattcaccttcagtacctttggc CDRH1 nuc SEQ ID NO: 74 atctggtatgatggaagtagtaaa CDRH2 nuc SEQ ID NO: 75 gtgaaagtcggagctaactggggatggaggtacttcgatctc CDRH3 nuc SEQ ID NO: 76 cagagcctcctacatagtgatggaaacacctat CDRL1 nuc SEQ ID NO: 77 gaagtttcc CDRL2 nuc SEQ ID NO: 78 ctgatctat gaagtttcc agccggttc CDRL2 long nuc SEQ ID NO: 79 atgcaaggcatacactcgtggacg CDRL3 nuc SEQ ID NO: 80 caggagcaactggtggagtctgggggaggcgtggtccagcctgggaagtccctgagactctcctgtgcagcctct ggattcaccttcagtacctttggc atgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagtc atctggtatgatggaagtagtaaa taccatgcagactccgtgaagggccgattc accatctccagagacaattccaagagcacgctgtatctgcaaatgaacagcctgagagctgaggacacggctatgtattactgt gtgaaagtcggagctaactggggatggaggtacttcgatctc tggggccgtggcaccctggtcaccgtctcctcag VH nuc SEQ ID NO: 81 gatattgtgatgacccagactccactctctctgtccgtcacccctggacagccggcctccatctcctgcaagtctagt cagagcctcctacatagtgatggaaacacctat ttgtcttggtacctgcagaagccaggccagtctccacagctcctgatctat gaagtttcc agccggttctctggagtgccagataggttcagc ggcagcgggtcagggacagatttcacactgaaaatcagccgggtggaggctgacgatgttggggtttactactgc atgcaaggcatacactcgtggacg ttcggccaagggaccaaggtggaaatcaaac VL nuc MGG4 SEQ ID NO: 82 GFRFSDYG CDRH1 aa SEQ ID NO: 83 IWYDGSNE CDRH2 aa SEQ ID NO: 84 AKLLVGITTDVFDV CDRH3 aa SEQ ID NO: 85 QSVLSSSNNKNY CDRL1 aa SEQ ID NO: 86 WAS CDRL2 aa SEQ ID NO: 87 LIY WAS TRE CDRL2 long aa SEQ ID NO: 88 QQYYTASPF CDRL3 aa SEQ ID NO: 89 QVQLVESGGGVVQPGRSLRLSCAAS GFRFSDYG MHWVRQAPGKGLEWVAL IWYDGSNE SYLDSVKGRFTISRDNSKNTLYLQMNNLRTEDTAVYYC AKLLVGITTDVFDV WGQGTVVTVSS VH aa SEQ ID NO: 90 DIVMTQSPDSLAVSLGERATINCRSS QSVLSSSNNKNY LAWYQHKPRQPPKLLIY WAS TRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC QQYYTASPF FGGGTKVEIK VL aa SEQ ID NO: 91 ggattcaggttcagtgactatggc CDRH1 nuc SEQ ID NO: 92 atatggtatgatggaagtaatgaa CDRH2 nuc SEQ ID NO: 93 gcgaaactactagtgggaattactactgatgttttttgatgtc CDRH3 nuc SEQ ID NO: 94 cagagtgttttatccagctccaacaataagaactac CDRL1 nuc SEQ ID NO: 95 tgggcatct CDRL2 nuc SEQ ID NO: 96 ctcatttac tgggcatct acccgggaa CDRL2 long nuc SEQ ID NO: 97 cagcaatattatactgcttccccatt CDRL3 nuc SEQ ID NO: 98 caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctct ggattcaggttcagtgactatggc atgcactgggtccgccaggctccgggcaaggggctggagtgggtggcactt atatggtatgatggaagtaatgaa tcctatttagactccgtgaagggccgattc accatctccagagacaattccaagaacacactgtatctgcaaatgaacaacctgagaactgaggacacggctgtgtattactgt gcgaaactactagtgggaattactactgatgtttttgatgtc tggggccaagggacagtggtcaccgtctcttcag VH nuc SEQ ID NO: 99 gacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccaccatcaactgcaggtccagc cagagtgttttatccagctccaacaataagaactac ttagcttggtaccagcacaaaccacgacagcctcctaaactgctcatttac tgggcatct acccgggaatccggggtccctgaccgattcagtggcagcggg tctgggacagatttcactctcaccatcagcagcctgcaggctgaagatgtggcagtttattactgt cagcaatattatactgcttccccattt ttcggcggagggaccaaggtagagatcaaac VL nuc MGG8 SEQ ID NO: 100 GFMISGSV CDRH1 aa SEQ ID NO: 101 IRDKANNEAT CDRH2 aa SEQ ID NO: 102 TRGIIVGDTWHFDP CDRH3 aa SEQ ID NO: 103 ESLLRSDGKTY CDRL1 aa SEQ ID NO: 104 EVS CDRL2 aa SEQ ID NO: 105 LMY EVS KRF CDRL2 long aa SEQ ID NO: 106 MQSIQLVT CDRL3 aa SEQ ID NO: 107 EVQLVESGGGLVQPGGSLKLSCAAS GFMISGSV LHWVRQASGKGLEWLGR IRDKANNEAT AYAASVKGRFTISRDDSKDTTYLQMNSLRIEDTAVYYC TRGIIVGDTWHFDP WGQGTLVTVSS VH aa SEQ ID NO: 108 DIVMTQTPLSLSVTPGQTASISCKSS ESLLRSDGKTY LYWYLQKPGQSPQLLMY EVS KRFSGVPDRFSGSGSGTDFTLKISRVETDDVGIYYC MQSIQLVT FGQGTKVEIK VL aa SEQ ID NO: 109 gggttcatgatcagtggctctgtt CDRH1 nuc SEQ ID NO: 110 attagagacaaagctaacaatgaggcgaca CDRH2 nuc SEQ ID NO: 111 acgaggggtatcatagtaggtgacacctggcacttcgacccc CDRH3 nuc SEQ ID NO: 112 gagagcctcctgagaagcgatggaaagaccta CDRL1 nuc SEQ ID NO: 113 gaagtttcc CDRL2 nuc SEQ ID NO: 114 ctgatgtat gaagtttcc aagcgcttc CDRL2 long nuc SEQ ID NO: 115 atgcaaagtatacagcttgtgact CDRL3 nuc SEQ ID NO: 116 gaagtgcagctggtggagtccgggggaggcctggtccagcctggggggtccctgaaactctcctgtgcagcctct gggttcatgatcagtggctctgtt ctacactgggtccgccaggcctccgggaaagggctggagtggcttggccgt attagagacaaagctaacaatgaggcgaca gcatatgcagcgtcggtgaaa ggcaggttcaccatctccagagatgattcaaaggacacgacatatctgcaaatgaacagcctgagaatcgaggacacggccgtgtattactgt acgaggggtatcatagtaggtgacacctggcacttcgacccc tggggccagggaaccctggtcaccgtctcctcag VH nuc SEQ ID NO: 117 gatattgtgatgacccagactccactctctctgtccgtcacccctggacagacggcctccatctcctgcaagtctagt gagagcctcctgagaagcgatggaaagacctac ttgtattggtatctgcagaagccaggccagtctccacagctcctgatgtat gaagtttcc aagcgcttctctggagtgccagataggttcagt ggcagcgggtcaggaacagattttacactgaaaatcagccgggtggagactgatgatgttggcatttattactgc atgcaaagtatacagcttgtgact ttcggccaagggaccaaggtggaaatcaaac VL nuc MGH1 SEQ ID NO: 118 GYTFTDYY CDRH1 aa SEQ ID NO: 119 INPYIGVS CDRH2 aa SEQ ID NO: 120 AACSNVGCYVY CDRH3 aa SEQ ID NO: 121 QSLVYSDGNTY CDRL1 aa SEQ ID NO: 122 KVS CDRL2 aa SEQ ID NO: 123 LIY KVS NRD CDRL2 long aa SEQ ID NO: 124 MQGTHWPDT CDRL3 aa SEQ ID NO: 125 QVQLVQSGAEVKKPGASVRVSCKTS GYTFTDYY VHWVRQAPGHGLECMGW INPYIGVS KYAQKFQGRVTLTRDTSISTAYMEISRLTSDDTAVYYC AACSNVGCYVY WGQGSLVTVSS VH aa SEQ ID NO: 126 DVVMTQSPLSLPVTLGQPASISCRSS QSLVYSDGNTY LNWFQQRPGQSPRRLIY KVS NRDSGVPDRFSGSGSGTDFTLKISRVEAEDVAIYFC MQGTHWPDT FGQGTKLEIK VL aa SEQ ID NO: 127 ggatacacgttcaccgactactat CDRH1 nuc SEQ ID NO: 128 atcaatccttacattggtgtctca CDRH2 nuc SEQ ID NO: 129 gcggcttgtagtaacgttggctgctacgtctat CDRH3 nuc SEQ ID NO: 130 caaagtctcgtgtacagtgatggaaacacctac CDRL1 nuc SEQ ID NO: 131 aaggtttct CDRL2 nuc SEQ ID NO: 132 ctaatttat aaggtttct aatcgggac CDRL2 long nuc SEQ ID NO: 133 atgcaaggtacacactggcctgacact CDRL3 nuc SEQ ID NO: 134 caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgagagtctcctgcaagacatct ggatacacgttcaccgactactat gtccactgggtgcgacaggccccaggacacgggcttgagtgcatgggctgg atcaatccttacattggtgtctca aagtatgcacagaagtttcagggcagggtca ccttgaccagggacacgtccatcagcacagcctacatggaaattagcaggctaacatctgacgacacggccgtctattactgt gcggcttgtagtaacgttggctgctacgtctat tggggccagggatcgctggtcaccgtctcctcag VH nuc SEQ ID NO: 135 gatgttgtgatgactcagtctccactctccctgcccgtcacccttggacagccggcctccatctcctgcaggtctagt caaagtctcgtgtacagtgatggaaacacctac ttgaattggtttcagcagaggccaggccaatctccaaggcgcctaatttat aaggtttct aatcgggactctggggtcccagacagatt cagcggcagtgggtcaggcactgatttcacactgaaaatcagcagggtggaggctgaggatgttgcgatttatttctgc atgcaaggtacacactggcctgacact tttggccaggggaccaaactggagatcaaac VL nuc MGH2 SEQ ID NO: 136 GFSFSSYA CDRH1 aa SEQ ID NO: 137 TRYDGSNK CDRH2 aa SEQ ID NO: 138 AKVGDGTVAGTIDY CDRH3 aa SEQ ID NO: 139 QSLVYSDGNTY CDRL1 aa SEQ ID NO: 140 KVS CDRL2 aa SEQ ID NO: 141 LIY KVS NRD CDRL2 long aa SEQ ID NO: 142 MQGTHWWT CDRL3 aa SEQ ID NO: 143 QVQLVESGGGVVQPGGSLRLSCTAS GFSFSSYA MHWVRQAPGKGLEWVAY TRYDGSNK FYLDSVQGRFTISRDNSKNTLYLEMDSLRLEDTAVYFC AKVGDGTVAGTIDY WGQGTLVTVSS VH aa SEQ ID NO: 144 YIVMTQSPLSLPVTLGQPASISCRSS QSLVYSDGNTY LNWYQQRPGQSPRRLIY KVS NRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC MQGTHWWT FGQGTKVEIK VL aa SEQ ID NO: 145 ggtttcagcttcagtagttatgcc CDRH1 nuc SEQ ID NO: 146 acacggtatgatggaagtaataag CDRH2 nuc SEQ ID NO: 147 gcgaaagtgggggacgggacagtggctggtactattgacta CDRH3 nuc SEQ ID NO: 148 caaagcctcgtatatagtgatggaaacacctac CDRL1 nuc SEQ ID NO: 149 aaggtttct CDRL2 nuc SEQ ID NO: 150 ctaatttat aaggtttct aatcgggac CDRL2 long nuc SEQ ID NO: 151 atgcaaggtacacactggtggacg CDRL3 nuc SEQ ID NO: 152 caggtgcagctggtggagtctgggggaggcgtggtccagcctggggggtccctgagactctcctgtacagcgtct ggtttcagcttcagtagttatgcc atgcactgggtccgccaggctccaggcaagggactggagtgggtggcatat acacggtatgatggaagtaataag ttctacctagactccgtgcagggccgatt caccatctccagagacaattccaagaacacgctgtatctggaaatggacagcctgagacttgaggacacggctgtctatttctgt gcgaaagtgggggacgggacagtggctggtactattgactac tggggccagggaacgctggtcaccgtctcctcag VH nuc SEQ ID NO: 153 tatattgtgatgactcagtctccactctccctgcccgtcacccttggacagccggcctccatctcctgcaggtctagt caaagcctcgtatatagtgatggaaacacctac ttgaattggtatcagcagaggccaggccaatctccaaggcgcctaatttat aaggtttct aatcgggactctggggtcccagacagatttagcggcag tgggtcaggcactgatttcacactgaaaatcagcagggtggaggctgaggatgttggggtttattactgc atgcaaggtacacactggtggacg ttcggccaagggaccaaggtggaaatcaaac VL nuc MGH3 SEQ ID NO: 154 GFTFSSYT CDRH1 aa SEQ ID NO: 155 ISSSGSYI CDRH2 aa SEQ ID NO: 156 ARNVLDSSGYPTYFDY CDRH3 aa SEQ ID NO: 157 QSLLYSNGYNY CDRL1 aa SEQ ID NO: 158 LGS CDRL2 aa SEQ ID NO: 159 LIY LGS NRA CDRL2 long aa SEQ ID NO: 160 MQAVQTPLT CDRL3 aa SEQ ID NO: 161 EVQLVESGGGLVKPGGSLRLSCAAS GFTFSSYT MNWVRQAPGKGLEWVSS ISSSGSYI YYADSVKGRCTISRDNAKNSLDLQMNSLRAEDAAVYYC ARNVLDSSGYPTYFDY WGQGTLVTVSS VH aa SEQ ID NO: 162 DIVMTQSPLSLPVTPGEPASISCRSS QSLLYSNGYNY LDWYVQKPGQSPRLLIY LGS NRASGVPDRFSGSGSGTDFTLRISRVEAEDVGFYYC MQAVQTPLT FGGGTKVEIK VL aa SEQ ID NO: 163 ggattcaccttcagtagttatacc CDRH1 nuc SEQ ID NO: 164 attagtagtagtggtagttacata CDRH2 nuc SEQ ID NO: 165 gcaagaaatgtcttggacagtagtggttaccccacgtactttgactat CDRH3 nuc SEQ ID NO: 166 agagcctcctatatagtaatggatacaactat CDRL1 nuc SEQ ID NO: 167 ttgggttct CDRL2 nuc SEQ ID NO: 168 ctgatctat ttgggttct aatcgggcc CDRL2 long nuc SEQ ID NO: 169 atgcaagctgtacaaactcccctcact CDRL3 nuc SEQ ID NO: 170 gaggtgcagctggtggagtctgggggaggcctggtcaagcctggggggtccctgagactctcctgtgcagcctct ggattcaccttcagtagttatacc atgaactgggtccgccaggctccagggaaggggctggagtgggtctcatcc attagtagtagtggtagttacata tattacgcagactcagtgaagggccgatgcaccatctccagagacaacg ccaagaactcactggatctgcaaatgaacagcctgagagccgaggacgcggctgtgtattactgt gcaagaaatgtcttggacagtagtggttaccccacgtactttgactat tggggccagggaacgctggtcaccgtctcctcag VH nuc SEQ ID NO: 171 gatattgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagt cagagcctcctatatagtaatggatacaactat ctggattggtacgtgcagaagccagggcagtctccacgcctcctgatctat ttgggttct aatcgggcctccggggtccctgacaggttcagtgg cagtggatcaggcacagattttacactgagaatcagcagagtggaggctgaggatgttgggttttattactgc atgcaagctgtacaaactcccctcact ttcggcggagggaccaaggtggagatcaaac VL nuc MGU1 SEQ ID NO: 172 GFAFSSYG CDRH1 aa SEQ ID NO: 173 IWHDGTNK CDRH2 aa SEQ ID NO: 174 AIWYLDSPDHGFDI CDRH3 aa SEQ ID NO: 175 NGHSSNA CDRL1 aa SEQ ID NO: 176 VNSDGSH CDRL2 aa SEQ ID NO: 177 QAWDSGIWV CDRL3 aa SEQ ID NO: 178 QVQLVESGGGVVQPGRSLRLSCAAS GFAFSSYG MNWVRQAPGKGLEWVAV IWHDGTNK YYRDSVKGRFIISRDNAKNTLYLQMDSLSAEDTAMYYC AIWYLDSPDHGFDI WGRGTMVTVSS VH aa SEQ ID NO: 179 QLVLTQSPSASASLGVSVTLTCTLN NGHSSNA IAWHQQQPGKGPRYLMK VNSDGSH NKGAAVPDRFSGSSSGTERHLTISSLQSDDEADYYC QAWDSGIWV FGGGTKLTVL VL aa SEQ ID NO: 180 ggattcgctttcagtagttatggc CDRH1 nuc SEQ ID NO: 181 atttggcatgatggcaccaataaa CDRH2 nuc SEQ ID NO: 182 gccatttggtatcttgatagtcctgatcatggtttcgatatc CDRH3 nuc SEQ ID NO: 183 aatggccacagttccaatgcc CDRL1 nuc SEQ ID NO: 184 gttaatagtgatggcagcca CDRL2 nuc SEQ ID NO: 185 caggcctgggacagtggcatttgggtt CDRL3 nuc SEQ ID NO: 186 caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcatgtgcagcctcc ggattcgctttcagtagttatggc atgaactgggtccgccaggctccaggcaagggactggagtgggtggcagtt atttggcatgatggcaccaataaa tactatagagactccgtgaagggccgattcatcatctccaga gacaatgccaagaacaccttgtatctgcaaatggacagcctgagcgctgaggacacggctatgtattactgt gccatttggtatcttgatagtcctgatcatggtttcgatatc tggggccgagggacaatggtcaccgtctcttcag VH nuc SEQ ID NO: 187 cagcttgtcctgactcaatcgccctctgcctctgcctccctgggagtctcggtcaccctcacctgtactctgaac aatggccacagttccaatgcc atcgcatggcatcaacagcagccagggaagggccctcgttatttgatgaag gttaatagtgatggcagccac aataagggggccgctgtccctgatcgcttctcaggct ctagttctgggactgagcgccacctcaccatctccagcctccagtctgacgatgaggctgactattattgt caggcctgggacagtggcatttgggtt ttcggcggagggaccaagttgaccgtcctag VL nuc MGU3 SEQ ID NO: 188 GFTFSDYN CDRH1 aa SEQ ID NO: 189 ISHSSSTT CDRH2 aa SEQ ID NO: 190 ARRLRPLSYSGRYRDY CDRH3 aa SEQ ID NO: 191 QDVSNY CDRL1 aa SEQ ID NO: 192 DAS CDRL2 aa SEQ ID NO: 193 LIY DAS TLQ CDRL2 long aa SEQ ID NO: 194 QQYDSLPLT CDRL3 aa SEQ ID NO: 195 EVLLVESGGGLVQPGGSLRLSCAAS GFTFSDYN MHWVRQAPGKGLEWLSY ISHSSSTT YYADSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC ARLRPLSYSGRYRDY WGQGTLVTVSS VH aa SEQ ID NO: 196 DIQMTQSPSSLSASVGDRVTITCQAS QDVSNY VNWYQQKPGKAPKVLIY DAS TLQTGVPSRFSGSGSGTDFTFSISSLQPEDIATYYC QQYDSLPLT FGGGTKVEIK VL aa SEQ ID NO: 197 ggattcaccttcagtgactataac CDRH1 nuc SEQ ID NO: 198 attagtcatagtagtagtaccaca CDRH2 nuc SEQ ID NO: 199 gcgagacttcgtcccttatcgtatagtggcaggtaccgcgactac CDRH3 nuc SEQ ID NO: 200 caggacgttagtaattat CDRL1 nuc SEQ ID NO: 201 gatgcatcc CDRL2 nuc SEQ ID NO: 202 ctgatctac gatgcatcc actttgcaa CDRL2 long nuc SEQ ID NO: 203 cagcagtatgatagcctcccactcact CDRL3 nuc SEQ ID NO: 204 gaggtgctactagtggagtctgggggaggcttggtacaacctggggggtccctgagactctcctgtgcagcctct ggattcaccttcagtgactataac atgcactgggtccgccaggctccagggaaggggctggagtggctttcatac attagtcatagtagtagtaccaca tactacgcagactctgtgaggggccgattcaccatctccagagacaatg ccaagaactcactgtatctgcaaatgaacagcctgagagccgaggacacggctgtgtattactgt gcgagacttcgtcccttatcgtatagtggcaggtaccgcgactac tggggccagggaacgctggtcaccgtctcctcag VH nuc SEQ ID NO: 205 gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggcgagt caggacgttagtaattat gtaaattggtatcagcagaaaccagggaaagcccctaaggtcctgatctac gatgcatcc actttgcaaacaggggtcccatcaaggttcagtggaagtggatcggggacagatttta ctttcagcatcagcagcctgcagcctgaagatattgcaacatattactgt cagcagtatgatagcctcccactcact ttcggcggagggaccaaggtggagatcaaac VL nuc MGU5 SEQ ID NO: 206 GFSFSSYG CDRH1 aa SEQ ID NO: 207 IWHDGTNK CDRH2 aa SEQ ID NO: 208 TKRAGWGDALDI CDRH3 aa SEQ ID NO: 209 QDISNY CDRL1 aa SEQ ID NO: 210 DAS CDRL2 aa SEQ ID NO: 211 LIY DAS NLE CDRL2 long aa SEQ ID NO: 212 QQQRI CDRL3 aa SEQ ID NO: 213 QVQLVESGGGVVQPGRSLRLSCAAS GFSFSSYG MHWVRQAPGKGLDWVAL IWHDGTNK FYTDSVKGRFTISRDNSKDTLFLQMNSLRVEDTAVYYC TKRAGWGDALDI WGQGTMVTVSS VH aa SEQ ID NO: 214 DIQMTQSPSSLSASVGDRVTITCQAS QDISNY LNWYQQKPGKAPKLLIY DAS NLETGVPSRFSGSGSATDFTLTISSLQSEDIATYYC QQQRI FGGGTKVEIK
VL aa SEQ ID NO: 215 ggattcagcttcagtagttatggc CDRH1 nuc SEQ ID NO: 216 atatggcatgatggaactaataaa CDRH2 nuc SEQ ID NO: 217 acgaagcgggctggctggggtgatgctcttgatatc CDRH3 nuc SEQ ID NO: 218 caggacattagcaactat CDRL1 nuc SEQ ID NO: 219 gatgcatcc CDRL2 nuc SEQ ID NO: 220 ctgatctac gatgcatcc aatttggaa CDRL2 long nuc SEQ ID NO: 221 caacaacaaaggatt CDRL3 nuc SEQ ID NO: 222 caggtgcagttggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctct ggattcagcttcagtagttatggc atgcactgggtccgccaggctccaggcaaggggctggattgggtggctctt atatggcatgatggaactaataaa ttttacacagactccgtgaagggccgattcaccat ctccagagacaattccaaggacacactgtttctgcaaatgaacagtctgagagttgaggacacggctgtgtattactgt acgaagcgggctggctggggtgatgctcttgatatc tggggccaagggacaatggtcaccgtctcttcag VH nuc SEQ ID NO: 223 gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggcgagt caggacattagcaactat ttaaattggtatcagcagaaaccagggaaagcccctaaactcctgatctac gatgcatcc aatttggaaacaggggtcccatcaaggttcagtggaagtggatctgcgacagattttact ctcaccatcagcagcctgcagtctgaagacattgcaacatattactgt caacaacaaaggatt ttcggcggagggaccaaggtggagatcaaac VL nuc MGU8 SEQ ID NO: 224 GFTFSNYG CDRH1 aa SEQ ID NO: 225 IWHDGTNK CDRH2 aa SEQ ID NO: 226 TKRGGWGDGSDI CDRH3 aa SEQ ID NO: 227 QDVDNY CDRL1 aa SEQ ID NO: 228 DAS CDRL2 aa SEQ ID NO: 229 LIY DAS NLA CDRL2 long aa SEQ ID NO: 230 QQQRI CDRL3 aa SEQ ID NO: 231 QVQLVESGGGVVQPGRSLRLSCAAG GFTFSNYG MHWVRQAPGKGLEWVAL IWHDGTNK FYADSVKGRFTISRDNSKNTLSLQMDSLTTEDTAIYFC TKRGGWGDGSDI WGQGTMVTVSS VH aa SEQ ID NO: 232 DIQMTQSPSSLSASVGDRVTITCQAS QDVDNY LNWYQHKPGKAPKLLIY DAS NLATGVPSRFSGSGSSTDFTLTISSLQSDDFATYYC QQQRI FGGGTRVEIK VL aa SEQ ID NO: 233 ggatttaccttcagtaactatggc CDRH1 nuc SEQ ID NO: 234 atatggcatgatggaactaataaa CDRH2 nuc SEQ ID NO: 235 acgaagcgaggtggctggggtgatggttctgatatc CDRH3 nuc SEQ ID NO: 236 caggacgttgacaactat CDRL1 nuc SEQ ID NO: 237 gatgcatcc CDRL2 nuc SEQ ID NO: 238 ctgatctac gatgcatcc aatttggcg CDRL2 long nuc SEQ ID NO: 239 caacaacaaaggatt CDRL3 nuc SEQ ID NO: 240 caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctaagactctcctgtgcagccggt ggatttaccttcagtaactatggc atgcactgggtccgccaggctccaggcaaggggctggagtgggtggcactt atatggcatgatggaactaataaa ttctatgcagactccgtgaagggccgattcacca tctccagagacaattccaagaacacgctgtctctgcaaatggacagcctgacaactgaggacacggctatatatttctgt acgaagcgaggtggctggggtgatggttctgatatc tggggccaagggacaatggtcaccgtctcttcag VH nuc SEQ ID NO: 241 gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggcgagt caggacgttgacaactat ttaaattggtatcagcataaaccagggaaagcccctaagctcctgatctac gatgcatcc aatttggcgacaggggtcccatcaaggttcagtggaagtggatcttcgacagatttta ctctcaccatcagcagcctgcagtctgatgactttgcaacatattactgt caacaacaaaggatt ttcggcggagggaccagggtggaaatcaaac VL nuc MGU10 SEQ ID NO: 242 GFAFSNYG CDRH1 aa SEQ ID NO: 243 IWHDGSLK CDRH2 aa SEQ ID NO: 244 TVWYLETPDDGFDI CDRH3 aa SEQ ID NO: 245 HGHTSKA CDRL1 aa SEQ ID NO: 246 VNSDGSH CDRL2 aa SEQ ID NO: 247 QAWDSGIWV CDRL3 aa SEQ ID NO: 248 QVQLVESGGGVVQPGRSLRLSCAAS GFAFSNYG MNWVRQAPGKGLEWVAV IWHDGSLK YYTQSVKGRFTISRDNAKNTLFLQMDSLSADDDTAMYYC TVWYLETPDDGFDI WGRGTMVTVSS VH aa SEQ ID NO: 249 QLVLTQPPSASASLGVSVTLTCTLS HGHTSKA IAWHQQQPGKGPRYLMK VNSDGSH TKGAAVPDRFSGSTSGAERHFTISNLQSDDEADYYC QAWDSGIWV FGGGTKLTVL VL aa SEQ ID NO: 250 ggattcgctttcagcaattatggc CDRH1 nuc SEQ ID NO: 251 atttggcatgacggcagtcttaaa CDRH2 nuc SEQ ID NO: 252 accgtttggtaccttgaaactcctgatgatggtttcgatatt CDRH3 nuc SEQ ID NO: 253 catggccacacctccaaagcc CDRL1 nuc SEQ ID NO: 254 gttaatagtgatggcagccac CDRL2 nuc SEQ ID NO: 255 caggcctgggacagtggcatttgggtt CDRL3 nuc SEQ ID NO: 256 caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctctcatgtgcagcctcc ggattcgctttcagcaattatggc atgaactgggtccgccaggctccaggcaagggactggaatgggtggcagtt atttggcatgacggcagtcttaaa tattatacacagtccgtgaagggccgattcacca tctccagagacaatgccaagaacacgttgtttctccaaatggacagcctgagcgctgacgacacggctatgtattattgt accgtttggtaccttgaaactcctgatgatggtttcgatatt tggggccgagggacaatggtcaccgtctcgtcag VH nuc SEQ ID NO: 257 cagcttgtcctgactcaaccgccctctgcctctgcctccctgggagtctcggtcaccctcacctgtactctgagt catggccacacctccaaagcc atcgcgtggcatcaacagcagccagggaagggccctcgttatttgatgaaa gttaatagtgatggcagccac actaagggggccgctgtccctgatcgcttctcaggct ctacttctggggctgagcgccacttcaccatctccaacctccagtctgacgatgaggctgattattattgt caggcctgggacagtggcatttgggtt ttcggcggagggaccaagttgaccgtcctag VL nuc MGU11 SEQ ID NO: 258 GFSFSSYG CDRH1 aa SEQ ID NO: 259 IWYDGTNK CDRH2 aa SEQ ID NO: 260 ANDIAGWGYDGSNA CDRH3 aa SEQ ID NO: 261 QSLVYSDGNTY CDRL1 aa SEQ ID NO: 262 KVS CDRL2 aa SEQ ID NO: 263 LIY KVS NRD CDRL2 long aa SEQ ID NO: 264 MQGTVGFT CDRL3 aa SEQ ID NO: 265 QVQLVESGGGVVQPGRSLRLSCVAS GFSFSSYG MHWVRQAPGKGLEWVAV IWYDGTNK YYADSVKGRFTISRDNTKNTLYLQMNSLRADDTAMYYC ANDIAGWGYDGSNA WGQGTLVTVSS VH aa SEQ ID NO: 266 LSLPVTPGQPASISCKSS QSLVYSDGNTY LNWFQQRPGQSPRRLIY KVS NRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC MQGTVGFT FGPGTTVDIK VL aa SEQ ID NO: 267 ggattcagcttcagtagctatggc CDRH1 nuc SEQ ID NO: 268 atatggtatgatggaaccaataaa CDRH2 nuc SEQ ID NO: 269 gcgaatgatattgcggggtggggctatgatggtagtaatgcc CDRH3 nuc SEQ ID NO: 270 caaagcctcgtatatagtgatggaaacacctac CDRL1 nuc SEQ ID NO: 271 aaggtttct CDRL2 nuc SEQ ID NO: 272 ctaatttat aaggtttct aaccgggac CDRL2 long nuc SEQ ID NO: 273 atgcaaggtacagtggggttcact CDRL3 nuc SEQ ID NO: 274 caggtgcagctggtggagtctgggggaggcgtagtccagcctgggaggtccctgagactctcctgcgtagcctct ggattcagcttcagtagctatggc atgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagtt atatggtatgatggaaccaataaa tactatgcagattccgtgaagggccgattcaccatct ccagagacaataccaagaacacgttgtacctgcaaatgaacagcctgagagcggacgacacggctatgtattactgt gcgaatgatattgcggggtggggctatgatggtagtaatgcc tggggccagggaaccctggtcaccgtctcctcag VH nuc SEQ ID NO: 275 ctctccctgcccgtcacccctggacagccggcctccatctcctgcaagtctagt caaagcctcgtatatagtgatggaaacacctac ttgaattggtttcagcagaggccaggccaatctccaaggcgcctaatttat aaggtttct aaccgggactctggggtcccagacagattcagcggcagtgggtcaggcactgattt cacactgaaaatcagcagggtggaggctgaggatgttggggtttattactgc atgcaaggtacagtggggttcact ttcggccctgggaccacagtggatatcaaac VL nuc MGU12 SEQ ID NO: 276 GFSFSSYG CDRH1 aa SEQ ID NO: 277 IWHDGSYS CDRH2 aa SEQ ID NO: 278 VKVEDYVRGSSHGGAFHI CDRH3 aa SEQ ID NO: 279 QTINNW CDRL1 aa SEQ ID NO: 280 KAS CDRL2 aa SEQ ID NO: 281 LIY KAS SLE CDRL2 long aa SEQ ID NO: 282 QQYSSYWT CDRL3 aa SEQ ID NO: 283 QVQLVESGGGVVQPGRSLRLSCAAS GFSFSSYG MHWVRQAPGKGPEWVAV IWHDGSYS YYADSVRGRFTISRDNSKNTLYLQMNSLRPEDTGMYHC VKVEDYVRGSSHGGAFHI WGQGTMVTVSS VH aa SEQ ID NO: 284 DIQMTQSPSTLSASVGDRVTITCRAS QTINNW LAWYQWKPGKAPELLIY KAS SLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYC QQYSSYWT FGQGTKVDIK VL aa SEQ ID NO: 285 ggattcagcttcagtagttatggc CDRH1 nuc SEQ ID NO: 286 atttggcatgatggaagttacagt CDRH2 nuc SEQ ID NO: 287 gtgaaagttgaggattacgttagggggagttcacatgggggtgcttttcatatc CDRH3 nuc SEQ ID NO: 288 cagactattaataactgg CDRL1 nuc SEQ ID NO: 289 t aaggcgtct CDRL2 nuc SEQ ID NO: 290 ctgatctat aaggcgtct agtttagaa CDRL2 long nuc SEQ ID NO: 291 caacagtatagtagttatattggacg CDRL3 nuc SEQ ID NO: 292 caggtacaactggtggaatctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctcc ggattcagcttcagtagttatggc atgcactgggtccgccaggctccaggcaaggggccggagtgggtggcagtg atttggcatgatggaagttacagt tactatgcagactccgtgaggggccgattcacca tctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagacctgaggacacggggatgtatcactgt gtgaaagttgaggattacgttagggggagttcacatgggggtgcttttcatatc tggggccaagggacaatggtcaccgtctcttcag VH nuc SEQ ID NO: 293 gacatccagatgacccagtctccttccaccctgtctgcatctgtaggggacagagtcaccatcacttgccgggccagt cagactattaataactgg ttggcctggtatcagtggaaaccggggaaagcccctgagctcctgatctat aaggcgtct agtttagaaagtggggtcccatcaaggttcagcggcagtggatctgggac agaattcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgc caacagtatagtagttattggacg ttcggccaagggaccaaggtggacatcaaac VL nuc MGV3 SEQ ID NO: 294 GFTVSDSY CDRH1 aa SEQ ID NO: 295 IYSGSST CDRH2 aa SEQ ID NO: 296 ARGPNDYRNRKYYYYMDV CDRH3 aa SEQ ID NO: 297 QSVDSPY CDRL1 aa SEQ ID NO: 298 GAS CDRL2 aa SEQ ID NO: 299 LIF GAS IRA CDRL2 long aa SEQ ID NO: 300 HQYGNAPYI CDRL3 aa SEQ ID NO: 301 EVQVVESGGDLVQPGGSLRLSCAVY GFTVSDSY MSWVRQAPGKGLEWVSV IYSGSST YYIDSVKGRFTISSRDRSKNTLYLQMNTLRVEDTALYYC ARGPNDYRNRKYYYYMDV WGKGTAVTVSS VH aa SEQ ID NO: 302 EIVLTQSPDTLSLSAGERVTLSCRAS QSVDSPY LAWYQQRPGQTPRLLIF GAS IRATDIPDRFSGGGSGTDFTLTISRLEPEDSGVYYC HQYGNAPYI FGQGTKLEIK VL aa SEQ ID NO: 303 ggattcaccgtcagtgacagctac CDRH1 nuc SEQ ID NO: 304 atctatagtggtagtagtaca CDRH2 nuc SEQ ID NO: 305 gcgagaggccctaatgactacagaaatcgcaaatattactactacatggacgtc CDRH3 nuc SEQ ID NO: 306 cagagtgttgacagtccctac CDRL1 nuc SEQ ID NO: 307 ggtgcctct CDRL2 nuc SEQ ID NO: 308 ctcattttt ggtgcctct attagggcc CDRL2 long nuc SEQ ID NO: 309 caccagtatggtaacgcaccctacatt CDRL3 nuc SEQ ID NO: 310 gaggtgcaggtggtggagtctgggggagacttggtccagccgggggggtccctgagactctcctgtgcagtctat ggattcaccgtcagtgacagctac atgagctgggtccgccaggctccggggaaggggctggagtgggtctcagtt atctatagtggtagtagtaca tactacatagactccgtgaagggccgattcaccatctccaga gacaggtccaagaacaccttgtatcttcaaatgaacaccctgagagttgaggacacggctctttattactgc gcgagaggccctaatgactacagaaatcgcaaatattactactacatggacgtc tggggcaaaggggaccgcggtcaccgtctcctcag VH nuc SEQ ID NO: 311 gaaattgtgttgacacagtctccagacaccctgtccttgtctgcaggggaaagagtcaccctctcttgcagggccagt cagagtgttgacagtccctac ttagcctggtatcagcaaagacctggccagactcccaggctcctcattttt ggtgcctct attagggccactgacatcccagacaggttcagtggcggtggg tctgggacagacttcactctcaccatcagcagactggaacctgaagattctggagtgtattactgt caccagtatggtaacgcaccctacatt tttggccaggggaccaagctggagatcaaac VL nuc SEQ ID NO: 312 KNNQGNGQGHNMPNDPNRNVDENANANSAVKNNNNEEPSDKHIKEYLNKIQNSLSTEWSPCSVTCGNGIQVRIKPGSANKPKDELDYANDIEKKICKMEKCS CSP C-terminal peptides 282 - 383 SEQ ID NO: 313 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK IgG1 CH1-CH2-CH3 aa SEQ ID NO: 314 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC IgG CK aa SEQ ID NO: 315 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS IgG CL aa SEQ ID NO: 316 gcgtcgaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacctgtgacggtctcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgt ggtgaccgtgccctccagcagcttgggcaccgagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggaccc ctgaggtcacatgcgtggtggtggacgtgagccacgaAgaCcctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtct ccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctgg actccgacggctccttcttcctctatagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtccccgggtaaa IgG1 CH1-CH2-CH3 nuc SEQ ID NO: 317 cgTacGgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcct cagcagcaccctgacgctgagcaaagcagactacgagaaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt IgG CK nuc SEQ ID NO: 318 ggtcagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagccaacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggcttggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggccagcagct atctgagcctgacgcctgagcagtggaagtcccacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcccctacagaatgttca IgG CL nuc SEQ ID NO: 319 MENITSGFLGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQSPTSNHSPTSCPPTCPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLIPGSSTTSTGPCRTCMTTAQGTSMYPSCCCTKPSDGNCTCIPIPSSWAFGKFLWEWASARFSWLSLLVPFVQWFVGLSPTVWLSVIWMMWYWGPSLYSILSPFLPLLPIFFCL WVYI HBsAg S domain SEQ ID NO: 320 MMRKLAILSVSSFLFVEALFQEYQCYGSSSNTRVLNELNYDNAGTNLYNELEMNYYGKQENWYSLKKNSRSLGENDDGNNEDNEKLRKPKHKKLKQPADGNPDP N-terminus of CSP SEQ ID NO: 321 KKLKQPA N-terminal region of CSP SEQ ID NO: 322 HKKLKQPAD N-terminal region of CSP SEQ ID NO: 323 KHKKLKQPADG N-terminal region of CSP SEQ ID NO: 324 KHKKLKQP N-terminal region of CSP SEQ ID NO: 325 RKPKHKKLKQP N-terminal region of CSP SEQ ID NO: 326 PKHKKLKQPADGN N-terminal region of CSP SEQ ID NO: 327 KPKHKKLKQPADGNP N-terminal region of CSP SEQ ID NO: 328 RKPKHKKLKQPADGNPD N-terminal region of CSP SEQ ID NO: 329 NEKLRKPKHKKLKQP N-terminal region of CSP SEQ ID NO: 330 NEKLRKPKHKKLKQPADG N-terminal region of CSP SEQ ID NO: 331 MLSKDIIKLLNEQVNKEMNSSNLYMSMSSWCYTHSLDGAGLFLFDHAAEEYEHAKKLIVFLNENNNVPVQLTSISAPEHKFEGLTQIFQKAYEHEQHISESINNIVDHAIKGKDHATFNFLQWYVAEQHEEEVLFKDILDKIELIGNENHGLYLADQYVKGIAKSRKS Ferritin polypeptide SEQ ID NO: 332 MEFLKRSFAPLTEKQWQEIDNRAREIFKTQLYGRKFVDVEGPYGWEYAAHPLGEVEVLSDENEVVKWGLRKSPLPLIELRATFTLDLWELDNLERGKPNVDLSSLEETVRKVAEFEDEVIFRGCEKSGVKGLLSFEERKIECGSTPKDLLEAIVRALSIFSKDGIEGPYTLVINTDRWINFLKEEAGHYPLEKRVEECLRGGKIITTPRIEDALV VSERGGDFKLILGQDLSIGYEDREKDAVRLFITETFTFQVVNPEALILLKF Encapsulin polypeptide:

The three sequences in bold in the VH/VL sequence represent CDR1, CDR2 and CDR3 in this order.

SEQUENCE LISTING <110> Institute for Research in Biomedicine <120> NOVEL MALARIA VACCINES AND ANTIBODIES BINDING TO PLASMODIUM SPOROZOITES <130> IR01P006WO, IMP193551 <150> US 62/487,266 <151> 2017-04-19 <160> 332 <170> PatentIn version 3.5 <210> 1 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 1 Asn Pro Asp Pro One <210> 2 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 2 Asn Pro Asp Pro Asn 1 5 <210> 3 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 3 Asn Pro Asp Pro Asn Ala 1 5 <210> 4 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 4 Asn Pro Asp Pro Asn Ala Asn 1 5 <210> 5 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 5 Asn Pro Asp Pro Asn Ala Asn Pro 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 6 Asn Pro Asp Pro Asn Ala Asn Pro Asn 1 5 <210> 7 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 7 Gly Asn Pro Asp Pro Asn Ala Asn Pro 1 5 <210> 8 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 8 Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn 1 5 10 <210> 9 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 9 Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro 1 5 10 <210> 10 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 10 Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys 1 5 10 <210> 11 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 11 Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn 1 5 10 <210> 12 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 12 Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys 1 5 10 <210> 13 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 13 Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys 1 5 10 <210> 14 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 14 Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn 1 5 10 <210> 15 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 15 Gln Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys 1 5 10 15 <210> 16 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 16 Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys 1 5 10 <210> 17 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 17 Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys 1 5 10 <210> 18 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 18 Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys Asn 1 5 10 <210> 19 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 19 Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys Asn 1 5 10 15 <210> 20 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 20 Gln Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys Asn 1 5 10 15 <210> 21 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 21 Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys Asn Asn 1 5 10 15 <210> 22 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CSP epitope <400> 22 Gln Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys Asn 1 5 10 15 Asn <210> 23 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> NPDP-peptide <400> 23 Lys Gln Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Lys 1 5 10 15 Asn Asn <210> 24 <211> 397 <212> PRT <213> Artificial Sequence <220> <223> PfCSP <400> 24 Met Met Arg Lys Leu Ala Ile Leu Ser Val Ser Ser Phe Leu Phe Val 1 5 10 15 Glu Ala Leu Phe Gln Glu Tyr Gln Cys Tyr Gly Ser Ser Ser Asn Thr 20 25 30 Arg Val Leu Asn Glu Leu Asn Tyr Asp Asn Ala Gly Thr Asn Leu Tyr 35 40 45 Asn Glu Leu Glu Met Asn Tyr Tyr Gly Lys Gln Glu Asn Trp Tyr Ser 50 55 60 Leu Lys Lys Asn Ser Arg Ser Leu Gly Glu Asn Asp Asp Gly Asn Asn 65 70 75 80 Glu Asp Asn Glu Lys Leu Arg Lys Pro Lys His Lys Lys Leu Lys Gln 85 90 95 Pro Ala Asp Gly Asn Pro Asp Pro Asn Ala Asn Pro Asn Val Asp Pro 100 105 110 Asn Ala Asn Pro Asn Val Asp Pro Asn Ala Asn Pro Asn Val Asp Pro 115 120 125 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 130 135 140 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 145 150 155 160 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 165 170 175 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 180 185 190 Asn Ala Asn Pro Asn Val Asp Pro Asn Ala Asn Pro Asn Ala Asn Pro 195 200 205 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 210 215 220 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 225 230 235 240 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 245 250 255 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 260 265 270 Asn Lys Asn Asn Gln Gly Asn Gly Gln Gly His Asn Met Pro Asn Asp 275 280 285 Pro Asn Arg Asn Val Asp Glu Asn Ala Asn Ala Asn Ser Ala Val Lys 290 295 300 Asn Asn Asn Asn Glu Glu Pro Ser Asp Lys His Ile Lys Glu Tyr Leu 305 310 315 320 Asn Lys Ile Gln Asn Ser Leu Ser Thr Glu Trp Ser Pro Cys Ser Val 325 330 335 Thr Cys Gly Asn Gly Ile Gln Val Arg Ile Lys Pro Gly Ser Ala Asn 340 345 350 Lys Pro Lys Asp Glu Leu Asp Tyr Ala Asn Asp Ile Glu Lys Lys Ile 355 360 365 Cys Lys Met Glu Lys Cys Ser Ser Val Phe Asn Val Val Asn Ser Ser 370 375 380 Ile Gly Leu Ile Met Val Leu Ser Phe Leu Phe Leu Asn 385 390 395 <210> 25 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CSP region I <400> 25 Lys Leu Lys Gln Pro 1 5 <210> 26 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> NANP-peptide <400> 26 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 1 5 10 15 Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro 20 25 30 Asn Ala Asn Pro Asn Ala Asn Pro 35 40 <210> 27 <211> 89 <212> PRT <213> Artificial Sequence <220> <223> 22-110-peptide <400> 27 Glu Tyr Gln Cys Tyr Gly Ser Ser Ser Asn Thr Arg Val Leu Asn Glu 1 5 10 15 Leu Asn Tyr Asp Asn Ala Gly Thr Asn Leu Tyr Asn Glu Leu Glu Met 20 25 30 Asn Tyr Tyr Gly Lys Gln Glu Asn Trp Tyr Ser Leu Lys Lys Asn Ser 35 40 45 Arg Ser Leu Gly Glu Asn Asp Asp Gly Asn Asn Glu Asp Asn Glu Lys 50 55 60 Leu Arg Lys Pro Lys His Lys Lys Leu Lys Gln Pro Ala Asp Gly Asn 65 70 75 80 Pro Asp Pro Asn Ala Asn Pro Asn Val 85 <210> 28 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG1 CDRH1 aa <400> 28 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 29 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG1 CDRH2 aa <400> 29 Ile Asn Trp Asn Gly Gly Ser Thr 1 5 <210> 30 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> MGG1 CDRH3 aa <400>30 Ala Arg Leu Gly Arg Ala Ala Arg Glu Tyr Tyr Tyr Tyr Tyr Met Asp 1 5 10 15 Val <210> 31 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG1 CDRL1 aa <400> 31 Ser Ser Asn Ile Gly Asn Asn Tyr 1 5 <210> 32 <400> 32 000 <210> 33 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGG1 CDRL2 long aa <400> 33 Leu Ile Tyr Asp Asn Lys Arg Pro 1 5 <210> 34 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> MGG1 CDRL3 aa <400> 34 Gly Thr Trp Asp Ser Ser Leu Ser Ala Gly Val 1 5 10 <210> 35 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> MGG1 VH aa <400> 35 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85 90 95 Ala Arg Leu Gly Arg Ala Ala Arg Glu Tyr Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 36 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> MGG1 VL aa <400> 36 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Ala Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 <210> 37 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG1 CDRH1 nuc <400> 37 ggattcacct ttgatgatta tgcc 24 <210> 38 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG1 CDRH2 nuc <400> 38 attaattgga atggtggtag caca 24 <210> 39 <211> 51 <212> DNA <213> Artificial Sequence <220> <223> MGG1 CDRH3 nuc <400> 39 gcgagacttg ggagagcagc ccgtgagtac tactactact acatggacgt c 51 <210> 40 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG1 CDRL1 nuc <400> 40 agctccaaca ttgggaataa ttat 24 <210> 41 <400> 41 000 <210> 42 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGG1 CDRL2 long nuc <400> 42 ctcatttatg acaataataa gcgaccc 27 <210> 43 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> MGG1 CDRL3 nuc <400> 43 ggcacatggg atagcagcct gagtgctgga gtg 33 <210> 44 <211> 372 <212> DNA <213> Artificial Sequence <220> <223> MGG1 VH nuc <400> 44 gaggtgcagc tggtggagtc tgggggaggt gtggtacggc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgagctgggt ccgccaagct 120 ccagggaagg ggctggagtg ggtctctggt attaattgga atggtggtag cacaggttat 180 gcagactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agccgaggac acggccttgt atcactgtgc gagacttggg 300 agagcagccc gtgagtacta ctactactac atggacgtct ggggcaaagg gaccacggtc 360 accgtctcct ca 372 <210> 45 <211> 336 <212> DNA <213> Artificial Sequence <220> <223> MGG1 VL nuc <400> 45 cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagaa ggtcaccatc 60 tcctgctctg gaagcagctc caacattggg aataattatg tatcctggta ccagcagctc 120 ccaggaacag cccccaaact cctcatttat gacaataata agcgaccctc agggattcct 180 gaccgattct ctggctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccgatta ttactgcggc acatgggata gcagcctgag tgctggagtg 300 ttcggcggag ggaccaagct gaccgtccta ggtcag 336 <210> 46 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG2 CDRH1 aa <400> 46 Gly Phe Thr Leu Asn Asn Tyr Trp 1 5 <210> 47 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG2 CDRH2 aa <400> 47 Ile Asn Ile Asp Gly Ser Thr Thr 1 5 <210> 48 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> MGG2 CDRH3 aa <400> 48 Ala Lys Gly Ser Ile Lys Ala Gly Gly Phe Trp Ser Gly Tyr Ser Asn 1 5 10 15 Trp Phe Asp Pro 20 <210> 49 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGG2 CDRL1 aa <400> 49 Pro Gly Pro Val Thr Ser Gly His Tyr 1 5 <210> 50 <400> 50 000 <210> 51 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGG2 CDRL2 long aa <400> 51 Leu Ile Tyr Asp Thr Ser Asn Lys His 1 5 <210> 52 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGG2 CDRL3 aa <400> 52 Leu Leu Ser Tyr Gly Gly Ala Pro Val 1 5 <210> 53 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> MGG2 VH aa <400> 53 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asn Asn Tyr 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ala His Ile Asn Ile Asp Gly Ser Thr Thr Thr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Ile Lys Ala Gly Gly Phe Trp Ser Gly Tyr Ser Asn 100 105 110 Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 54 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> MGG2 VL aa <400> 54 Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Asp Ser Asp Pro Gly Pro Val Thr Ser Gly 20 25 30 His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Val Pro Arg Thr 35 40 45 Leu Ile Tyr Asp Thr Ser Asn Lys His Ser Trp Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Leu Ser Tyr Gly Gly 85 90 95 Ala Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 55 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG2 CDRH1 nuc <400> 55 ggattcaccc tcaatacta ctgg 24 <210> 56 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG2 CDRH2 nuc <400> 56 attaatatcg atggcagtac taca 24 <210> 57 <211> 60 <212> DNA <213> Artificial Sequence <220> <223> MGG2 CDRH3 nuc <400> 57 gcaaagggaa gtattaaggc cggaggtttt tggagtggtt actccaactg gttcgacccc 60 <210> 58 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGG2 CDRL1 nuc <400> 58 cctggacctg tcaccagtgg tcattat 27 <210> 59 <400> 59 000 <210>60 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGG2 CDRL2 long nuc <400>60 ctgatttatg ataccagcaa caaacac 27 <210> 61 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGG2 CDRL3 nuc <400> 61 ctgctctcgt atggtggtgc ccctgta 27 <210> 62 <211> 382 <212> DNA <213> Artificial Sequence <220> <223> MGG2 VH nuc <400>62 gaggtgcagc tggtggagtc cgggggaggc ttagttcagc cggggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccctcaat aactactgga tgcactgggt ccgccaagct 120 ccagggaagg ggctggtctg ggtcgcacat attaatatcg atggcagtac tacaacctac 180 gcggactccg tgaagggccg attcaccatc tccagagaca acgccaagaa cacgctgtat 240 ctgcaaatga acagtctgag agccgaggac acggctgtct attactgtgc aaagggaagt 300 attaaggccg gaggtttttg gagtggttac tccaactggt tcgacccctg gggccaggga 360 accctggtca ccgtctcctc ag 382 <210> 63 <211> 328 <212> DNA <213> Artificial Sequence <220> <223> MGG2 VL nuc <400> 63 caggctgtgg tgactcagga gccctcactg actgtgtccc caggagggac agtcactctc 60 acctgtgact ccgaccctgg acctgtcacc agtggtcatt atccctactg gttccagcag 120 aagcctggcc aagtccccag gacactgatt tatgatacca gcaacaaaca ctcctggaca 180 cctgcccggt tttcaggctc cctccttggg ggcaaagctg ccctgaccct ttcgggtgcg 240 cagcctgagg atgaggctga ctattactgc ctgctctcgt atggtggtgc ccctgtattc 300 ggcgggaggga ccaaactgac cgtcctaa 328 <210> 64 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG3 CDRH1 aa <400>64 Gly Phe Thr Phe Ser Thr Phe Gly 1 5 <210> 65 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG3 CDRH2 aa <400>65 Ile Trp Tyr Asp Gly Ser Ser Lys 1 5 <210> 66 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MGG3 CDRH3 aa <400> 66 Val Lys Val Gly Ala Asn Trp Gly Trp Arg Tyr Phe Asp Leu 1 5 10 <210> 67 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> MGG3 CDRL1 aa <400> 67 Gln Ser Leu Leu His Ser Asp Gly Asn Thr Tyr 1 5 10 <210> 68 <400> 68 000 <210> 69 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGG3 CDRL2 long aa <400> 69 Leu Ile Tyr Glu Val Ser Ser Arg Phe 1 5 <210>70 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG3 CDRL3 aa <400>70 Met Gln Gly Ile His Ser Trp Thr 1 5 <210> 71 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> MGG3 VH aa <400> 71 Gln Glu Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Lys 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Ser Lys Tyr His Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Lys Val Gly Ala Asn Trp Gly Trp Arg Tyr Phe Asp Leu Trp Gly 100 105 110 Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 72 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> MGG3 VL aa <400> 72 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Asp Gly Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Glu Val Ser Ser Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Asp Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95 Ile His Ser Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 73 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> MGG3 CDRH1 nuc <400> 73 gattcacctt cagtaccttt ggc 23 <210> 74 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG3 CDRH2 nuc <400> 74 atctggtatg atggaagtag taaa 24 <210> 75 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> MGG3 CDRH3 nuc <400> 75 gtgaaagtcg gagctaactg gggatggagg tacttcgatc tc 42 <210> 76 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> MGG3 CDRL1 nuc <400> 76 cagaagcctcc tacatagtga tggaaacacc tat 33 <210> 77 <400> 77 000 <210> 78 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGG3 CDRL2 long nuc <400> 78 ctgatctatg aagtttccag ccggttc 27 <210> 79 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG3 CDRL3 nuc <400> 79 atgcaaggca tacactcgtg gacg 24 <210>80 <211> 364 <212> DNA <213> Artificial Sequence <220> <223> MGG3 VH nuc <400>80 caggagcaac tggtggagtc tgggggaggc gtggtccagc ctgggaagtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt acctttggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtc atctggtatg atggaagtag taaataccat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagag cacgctgtat 240 ctgcaaatga acagcctgag agctgaggac acggctatgt attactgtgt gaaagtcgga 300 gctaactggg gatggaggta cttcgatctc tggggccgtg gcaccctggt caccgtctcc 360 tcag 364 <210> 81 <211> 334 <212> DNA <213> Artificial Sequence <220> <223> MGG3 VL nuc <400> 81 gatattgtga tgacccagac tccactctct ctgtccgtca cccctggaca gccggcctcc 60 atctcctgca agtctagtca gagcctccta catagtgatg gaaacaccta tttgtcttgg 120 tacctgcaga agccaggcca gtctccacag ctcctgatct atgaagtttc cagccggttc 180 tctggagtgc cagataggtt cagcggcagc gggtcaggga cagatttcac actgaaaatc 240 agccgggtgg aggctgacga tgttggggtt tactactgca tgcaaggcat acactcgtgg 300 acgttcggcc aagggaccaa ggtggaaatc aaac 334 <210> 82 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG4 CDRH1 aa <400> 82 Gly Phe Arg Phe Ser Asp Tyr Gly 1 5 <210> 83 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG4 CDRH2 aa <400> 83 Ile Trp Tyr Asp Gly Ser Asn Glu 1 5 <210> 84 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MGG4 CDRH3 aa <400> 84 Ala Lys Leu Leu Val Gly Ile Thr Thr Asp Val Phe Asp Val 1 5 10 <210> 85 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> MGG4 CDRL1 aa <400> 85 Gln Ser Val Leu Ser Ser Ser Asn Asn Lys Asn Tyr 1 5 10 <210> 86 <400> 86 000 <210> 87 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGG4 CDRL2 long aa <400> 87 Leu Ile Tyr Trp Ala Ser Thr Arg Glu 1 5 <210> 88 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGG4 CDRL3 aa <400> 88 Gln Gln Tyr Tyr Thr Ala Ser Pro Phe 1 5 <210> 89 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> MGG4 VH aa <400> 89 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Arg Phe Ser Asp Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile Trp Tyr Asp Gly Ser Asn Glu Ser Tyr Leu Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Leu Val Gly Ile Thr Thr Asp Val Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Val Val Thr Val Ser Ser 115 120 <210> 90 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> MGG4 VL aa <400>90 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Val Leu Ser Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln His Lys Pro Arg Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Thr Ala Ser Pro Phe Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110 Lys <210> 91 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG4 CDRH1 nuc <400> 91 ggattcaggt tcagtgacta tggc 24 <210> 92 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG4 CDRH2 nuc <400> 92 atatggtatg atggaagtaa tgaa 24 <210> 93 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> MGG4 CDRH3 nuc <400> 93 gcgaaactac tagtgggaat tactactgat gtttttgatg tc 42 <210> 94 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> MGG4 CDRL1 nuc <400> 94 cagagtgttt tatccagctc caacaataag aactac 36 <210> 95 <400> 95 000 <210> 96 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGG4 CDRL2 long nuc <400> 96 ctcatttact gggcatctac ccgggaa 27 <210> 97 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> MGG4 CDRL3 nuc <400> 97 cagcaatatt atactgcttc cccatt 26 <210> 98 <211> 364 <212> DNA <213> Artificial Sequence <220> <223> MGG4 VH nuc <400> 98 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caggttcagt gactatggca tgcactgggt ccgccaggct 120 ccgggcaagg ggctggagtg ggtggcactt atatggtatg atggaagtaa tgaatcctat 180 ttagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacactgtat 240 ctgcaaatga acaacctgag aactgaggac acggctgtgt attactgtgc gaaactacta 300 gtgggaatta ctactgatgt ttttgatgtc tggggccaag ggacagtggt caccgtctct 360 tcag 364 <210> 99 <211> 340 <212> DNA <213> Artificial Sequence <220> <223> MGG4 VL nuc <400> 99 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca ggtccagcca gagtgtttta tccagctcca acaataagaa ctacttagct 120 tggtaccagc acaaaccacg acagcctcct aaactgctca tttactgggc atctacccgg 180 gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttatact gtcagcaata ttatactgct 300 tccccatttt tcggcggagg gaccaaggta gagatcaaac 340 <210> 100 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG8 CDRH1 aa <400> 100 Gly Phe Met Ile Ser Gly Ser Val 1 5 <210> 101 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> MGG8 CDRH2 aa <400> 101 Ile Arg Asp Lys Ala Asn Asn Glu Ala Thr 1 5 10 <210> 102 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MGG8 CDRH3 aa <400> 102 Thr Arg Gly Ile Ile Val Gly Asp Thr Trp His Phe Asp Pro 1 5 10 <210> 103 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> MGG8 CDRL1 aa <400> 103 Glu Ser Leu Leu Arg Ser Asp Gly Lys Thr Tyr 1 5 10 <210> 104 <400> 104 000 <210> 105 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGG8 CDRL2 long aa <400> 105 Leu Met Tyr Glu Val Ser Lys Arg Phe 1 5 <210> 106 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGG8 CDRL3 aa <400> 106 Met Gln Ser Ile Gln Leu Val Thr 1 5 <210> 107 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> MGG8 VH aa <400> 107 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Met Ile Ser Gly Ser 20 25 30 Val Leu His Trp Val Arg Gln Ala Ser Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Arg Ile Arg Asp Lys Ala Asn Asn Glu Ala Thr Ala Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asp Thr 65 70 75 80 Thr Tyr Leu Gln Met Asn Ser Leu Arg Ile Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Arg Gly Ile Ile Val Gly Asp Thr Trp His Phe Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 108 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> MGG8 VL aa <400> 108 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Thr Ala Ser Ile Ser Cys Lys Ser Ser Glu Ser Leu Leu Arg Ser 20 25 30 Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Met Tyr Glu Val Ser Lys Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Thr Asp Asp Val Gly Ile Tyr Tyr Cys Met Gln Ser 85 90 95 Ile Gln Leu Val Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 109 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG8 CDRH1 nuc <400> 109 gggttcatga tcagtggctc tgtt 24 <210> 110 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> MGG8 CDRH2 nuc <400> 110 attagagaca aagctaaacaa tgaggcgaca 30 <210> 111 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> MGG8 CDRH3 nuc <400> 111 acgaggggta tcatagtagg tgacacctgg cacttcgacc cc 42 <210> 112 <211> 32 <212> DNA <213> Artificial Sequence <220> <223> MGG8 CDRL1 nuc <400> 112 gagagcctcc tgagaagcga tggaaagacc ta 32 <210> 113 <400> 113 000 <210> 114 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGG8 CDRL2 long nuc <400> 114 ctgatgtatg aagtttccaa gcgcttc 27 <210> 115 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGG8 CDRL3 nuc <400> 115 atgcaaagta tacagcttgt gact 24 <210> 116 <211> 370 <212> DNA <213> Artificial Sequence <220> <223> MGG8 VH nuc <400> 116 gaagtgcagc tggtggagtc cgggggaggc ctggtccagc ctggggggtc cctgaaactc 60 tcctgtgcag cctctgggtt catgatcagt ggctctgttc tacactgggt ccgccaggcc 120 tccgggaaag ggctggagtg gcttggccgt attagagaca aagctaaacaa tgaggcgaca 180 gcatatgcag cgtcggtgaa aggcaggttc accatctcca gagatgattc aaaggacacg 240 acatatctgc aaatgaacag cctgagaatc gaggacacgg ccgtgtatta ctgtacgagg 300 ggtatcatag taggtgacac ctggcacttc gacccctggg gccagggaac cctggtcacc 360 gtctcctcag 370 <210> 117 <211> 334 <212> DNA <213> Artificial Sequence <220> <223> MGG8 VL nuc <400> 117 gatattgtga tgacccagac tccactctct ctgtccgtca cccctggaca gacggcctcc 60 atctcctgca agtctagtga gagcctcctg agaagcgatg gaaagaccta cttgtattgg 120 tatctgcaga agccaggcca gtctccacag ctcctgatgt atgaagtttc caagcgcttc 180 tctggagtgc cagataggtt cagtggcagc gggtcaggaa cagattttac actgaaaatc 240 agccgggtgg agactgatga tgttggcatt tattactgca tgcaaagtat acagcttgtg 300 actttcggcc aagggaccaa ggtggaaatc aaac 334 <210> 118 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGH1 CDRH1 aa <400> 118 Gly Tyr Thr Phe Thr Asp Tyr Tyr 1 5 <210> 119 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGH1 CDRH2 aa <400> 119 Ile Asn Pro Tyr Ile Gly Val Ser 1 5 <210> 120 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> MGH1 CDRH3 aa <400> 120 Ala Ala Cys Ser Asn Val Gly Cys Tyr Val Tyr 1 5 10 <210> 121 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> MGH1 CDRL1 aa <400> 121 Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr 1 5 10 <210> 122 <400> 122 000 <210> 123 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGH1 CDRL2 long aa <400> 123 Leu Ile Tyr Lys Val Ser Asn Arg Asp 1 5 <210> 124 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGH1 CDRL3 aa <400> 124 Met Gln Gly Thr His Trp Pro Asp Thr 1 5 <210> 125 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> MGH1 VH aa <400> 125 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Arg Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Val His Trp Val Arg Gln Ala Pro Gly His Gly Leu Glu Cys Met 35 40 45 Gly Trp Ile Asn Pro Tyr Ile Gly Val Ser Lys Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Ile Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Cys Ser Asn Val Gly Cys Tyr Val Tyr Trp Gly Gln Gly Ser 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 126 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> MGH1 VL aa <400> 126 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30 Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45 Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Ala Ile Tyr Phe Cys Met Gln Gly 85 90 95 Thr His Trp Pro Asp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 127 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGH1 CDRH1 nuc <400> 127 ggatacacgt tcaccgacta ctat 24 <210> 128 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGH1 CDRH2 nuc <400> 128 atcaatcctt acattggtgt ctca 24 <210> 129 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> MGH1 CDRH3 nuc <400> 129 gcggcttgta gtaacgttgg ctgctacgtc tat 33 <210> 130 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> MGH1 CDRL1 nuc <400> 130 caaagtctcg tgtacagtga tggaaacacc tac 33 <210> 131 <400> 131 000 <210> 132 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGH1 CDRL2 long nuc <400> 132 ctaatttata aggtttctaa tcgggac 27 <210> 133 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGH1 CDRL3 nuc <400> 133 atgcaaggta cacactggcc tgacact 27 <210> 134 <211> 355 <212> DNA <213> Artificial Sequence <220> <223> MGH1 VH nuc <400> 134 caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgagagtc 60 tcctgcaaga catctggata cacgttcacc gactactatg tccactgggt gcgacaggcc 120 ccaggacacg ggcttgagtg catgggctgg atcaatcctt acattggtgt ctcaaagtat 180 gcacagaagt ttcagggcag ggtcaccttg accagggaca cgtccatcag cacagcctac 240 atggaaatta gcaggctaac atctgacgac acggccgtct attactgtgc ggcttgtagt 300 aacgttggct gctacgtcta ttggggccag ggatcgctgg tcaccgtctc ctcag 355 <210> 135 <211> 337 <212> DNA <213> Artificial Sequence <220> <223> MGH1 VL nuc <400> 135 gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60 atctcctgca ggtctagtca aagtctcgtg tacagtgatg gaaacaccta cttgaattgg 120 tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taatcgggac 180 tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240 agcagggtgg aggctgagga tgttgcgatt tatttctgca tgcaaggtac acactggcct 300 gacacttttg gccaggggac caaactggag atcaaac 337 <210> 136 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGH2 CDRH1 aa <400> 136 Gly Phe Ser Phe Ser Ser Tyr Ala 1 5 <210> 137 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGH2 CDRH2 aa <400> 137 Thr Arg Tyr Asp Gly Ser Asn Lys 1 5 <210> 138 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MGH2 CDRH3 aa <400> 138 Ala Lys Val Gly Asp Gly Thr Val Ala Gly Thr Ile Asp Tyr 1 5 10 <210> 139 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> MGH2 CDRL1 aa <400> 139 Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr 1 5 10 <210> 140 <400> 140 000 <210> 141 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGH2 CDRL2 long aa <400> 141 Leu Ile Tyr Lys Val Ser Asn Arg Asp 1 5 <210> 142 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGH2 CDRL3 aa <400> 142 Met Gln Gly Thr His Trp Trp Thr 1 5 <210> 143 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> MGH2 VH aa <400> 143 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Thr Arg Tyr Asp Gly Ser Asn Lys Phe Tyr Leu Asp Ser Val 50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Asp Ser Leu Arg Leu Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Lys Val Gly Asp Gly Thr Val Ala Gly Thr Ile Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 144 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> MGH2 VL aa <400> 144 Tyr Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30 Asp Gly Asn Thr Tyr Leu Asn Trp Tyr Gln Gln Arg Pro Gly Gln Ser 35 40 45 Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95 Thr His Trp Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 145 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGH2 CDRH1 nuc <400> 145 ggtttcagct tcagtagtta tgcc 24 <210> 146 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGH2 CDRH2 nuc <400> 146 acacggtatg atggaagtaa taag 24 <210> 147 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> MGH2 CDRH3 nuc <400> 147 gcgaaagtgg gggacgggac agtggctggt actattgact a 41 <210> 148 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> MGH2 CDRL1 nuc <400> 148 caaaagcctcg tatatagtga tggaaacacc tac 33 <210> 149 <400> 149 000 <210> 150 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGH2 CDRL2 long nuc <400> 150 ctaatttata aggtttctaa tcgggac 27 <210> 151 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGH2 CDRL3 nuc <400> 151 atgcaaggta cacactggtg gacg 24 <210> 152 <211> 364 <212> DNA <213> Artificial Sequence <220> <223> MGH2 VH nuc <400> 152 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctggggggtc cctgagactc 60 tcctgtacag cgtctggttt cagcttcagt agttatgcca tgcactgggt ccgccaggct 120 ccaggcaagg gactggagtg ggtggcatat acacggtatg atggaagtaa taagttctac 180 ctagactccg tgcagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctggaaatgg acagcctgag acttgaggac acggctgtct atttctgtgc gaaagtgggg 300 gacgggacag tggctggtac tattgactac tggggccagg gaacgctggt caccgtctcc 360 tcag 364 <210> 153 <211> 334 <212> DNA <213> Artificial Sequence <220> <223> MGH2 VL nuc <400> 153 tatattgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60 atctcctgca ggtctagtca aagcctcgta tatagtgatg gaaacaccta cttgaattgg 120 tatcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taatcgggac 180 tctggggtcc cagacagatt tagcggcagt gggtcaggca ctgatttcac actgaaaatc 240 agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggtgg 300 acgttcggcc aagggaccaa ggtggaaatc aaac 334 <210> 154 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGH3 CDRH1 aa <400> 154 Gly Phe Thr Phe Ser Ser Tyr Thr 1 5 <210> 155 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGH3 CDRH2 aa <400> 155 Ile Ser Ser Ser Gly Ser Tyr Ile 1 5 <210> 156 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> MGH3 CDRH3 aa <400> 156 Ala Arg Asn Val Leu Asp Ser Ser Gly Tyr Pro Thr Tyr Phe Asp Tyr 1 5 10 15 <210> 157 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> MGH3 CDRL1 aa <400> 157 Gln Ser Leu Leu Tyr Ser Asn Gly Tyr Asn Tyr 1 5 10 <210> 158 <400> 158 000 <210> 159 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGH3 CDRL2 long aa <400> 159 Leu Ile Tyr Leu Gly Ser Asn Arg Ala 1 5 <210> 160 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGH3 CDRL3 aa <400> 160 Met Gln Ala Val Gln Thr Pro Leu Thr 1 5 <210> 161 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> MGH3 VH aa <400> 161 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Gly Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Cys Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Asp 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Val Leu Asp Ser Ser Gly Tyr Pro Thr Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 162 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> MGH3 VL aa <400> 162 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Val Gln Lys Pro Gly Gln Ser 35 40 45 Pro Arg Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala 85 90 95 Val Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 163 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGH3 CDRH1 nuc <400> 163 ggattcacct tcagtagtta tacc 24 <210> 164 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGH3 CDRH2 nuc <400> 164 attagtagta gtggtagtta cata 24 <210> 165 <211> 48 <212> DNA <213> Artificial Sequence <220> <223> MGH3 CDRH3 nuc <400> 165 gcaagaaatg tcttggacag tagtggttac cccacgtact ttgactat 48 <210> 166 <211> 32 <212> DNA <213> Artificial Sequence <220> <223> MGH3 CDRL1 nuc <400> 166 agagcctcct atatagtaat ggatacaact at 32 <210> 167 <400> 167 000 <210> 168 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGH3 CDRL2 long nuc <400> 168 ctgatctatt tgggttctaa tcgggcc 27 <210> 169 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGH3 CDRL3 nuc <400> 169 atgcaagctg tacaaactcc cctcact 27 <210> 170 <211> 370 <212> DNA <213> Artificial Sequence <220> <223> MGH3 VH nuc <400> 170 gaggtgcagc tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agttatacca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcatcc attagtagta gtggtagtta catatattac 180 gcagactcag tgaagggccg atgcaccatc tccagagaca acgccaagaa ctcactggat 240 ctgcaaatga acagcctgag agccgaggac gcggctgtgt attactgtgc aagaaatgtc 300 ttggacagta gtggttaccc cacgtacttt gactattggg gccagggaac gctggtcacc 360 gtctcctcag 370 <210> 171 <211> 337 <212> DNA <213> Artificial Sequence <220> <223> MGH3 VL nuc <400> 171 gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60 atctcctgca ggtctagtca gagcctccta tatagtaatg gatacaacta tctggattgg 120 tacgtgcaga agccagggca gtctccacgc ctcctgatct atttgggttc taatcgggcc 180 tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgagaatc 240 agcagagtgg aggctgagga tgttgggttt tattactgca tgcaagctgt acaaactccc 300 ctcactttcg gcggagggac caaggtggag atcaaac 337 <210> 172 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU1 CDRH1 aa <400> 172 Gly Phe Ala Phe Ser Ser Tyr Gly 1 5 <210> 173 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU1 CDRH2 aa <400> 173 Ile Trp His Asp Gly Thr Asn Lys 1 5 <210> 174 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MGU1 CDRH3 aa <400> 174 Ala Ile Trp Tyr Leu Asp Ser Pro Asp His Gly Phe Asp Ile 1 5 10 <210> 175 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> MGU1 CDRL1 aa <400> 175 Asn Gly His Ser Ser Asn Ala 1 5 <210> 176 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> MGU1 CDRL2 aa <400> 176 Val Asn Ser Asp Gly Ser His 1 5 <210> 177 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGU1 CDRL3 aa <400> 177 Gln Ala Trp Asp Ser Gly Ile Trp Val 1 5 <210> 178 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> MGU1 VH aa <400> 178 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp His Asp Gly Thr Asn Lys Tyr Tyr Arg Asp Ser Val 50 55 60 Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Ser Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ile Trp Tyr Leu Asp Ser Pro Asp His Gly Phe Asp Ile Trp Gly 100 105 110 Arg Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 179 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> MGU1 VL aa <400> 179 Gln Leu Val Leu Thr Gln Ser Pro Ser Ala Ser Ala Ser Leu Gly Val 1 5 10 15 Ser Val Thr Leu Thr Cys Thr Leu Asn Asn Gly His Ser Ser Asn Ala 20 25 30 Ile Ala Trp His Gln Gln Gln Pro Gly Lys Gly Pro Arg Tyr Leu Met 35 40 45 Lys Val Asn Ser Asp Gly Ser His Asn Lys Gly Ala Ala Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Ser Ser Gly Thr Glu Arg His Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp 85 90 95 Ser Gly Ile Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 180 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU1 CDRH1 nuc <400> 180 ggattcgctt tcagtagtta tggc 24 <210> 181 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU1 CDRH2 nuc <400> 181 atttggcatg atggcaccaa taaa 24 <210> 182 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> MGU1 CDRH3 nuc <400> 182 gccatttggt atcttgatag tcctgatcat ggtttcgata tc 42 <210> 183 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MGU1 CDRL1 nuc <400> 183 aatggccaca gttccaatgc c 21 <210> 184 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> MGU1 CDRL2 nuc <400> 184 gttaatagtg atggcagcca 20 <210> 185 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGU1 CDRL3 nuc <400> 185 caggcctggg acagtggcat ttgggtt 27 <210> 186 <211> 364 <212> DNA <213> Artificial Sequence <220> <223> MGU1 VH nuc <400> 186 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcatgtgcag cctccggatt cgctttcagt agttatggca tgaactgggt ccgccaggct 120 ccaggcaagg gactggagtg ggtggcagtt atttggcatg atggcaccaa taaatactat 180 agagactccg tgaagggccg attcatcatc tccagagaca atgccaagaa caccttgtat 240 ctgcaaatgg acagcctgag cgctgaggac acggctatgt attactgtgc catttggtat 300 cttgatagtc ctgatcatgg tttcgatatc tggggccgag ggacaatggt caccgtctct 360 tcag 364 <210> 187 <211> 334 <212> DNA <213> Artificial Sequence <220> <223> MGU1 VL nuc <400> 187 cagcttgtcc tgactcaatc gccctctgcc tctgcctccc tggggagtctc ggtcaccctc 60 acctgtactc tgaacaatgg ccacagttcc aatgccatcg catggcatca acagcagcca 120 gggaagggcc ctcgttatt gatgaaggtt aatagtgatg gcagccacaa taagggggcc 180 gctgtccctg atcgcttctc aggctctagt tctgggactg agcgccacct caccatctcc 240 agcctccagt ctgacgatga ggctgactat tattgtcagg cctgggacag tggcatttgg 300 gttttcggcg gagggaccaa gttgaccgtc ctag 334 <210> 188 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU3 CDRH1 aa <400> 188 Gly Phe Thr Phe Ser Asp Tyr Asn 1 5 <210> 189 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU3 CDRH2 aa <400> 189 Ile Ser His Ser Ser Ser Thr Thr 1 5 <210> 190 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> MGU3 CDRH3 aa <400> 190 Ala Arg Leu Arg Pro Leu Ser Tyr Ser Gly Arg Tyr Arg Asp Tyr 1 5 10 15 <210> 191 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> MGU3 CDRL1 aa <400> 191 Gln Asp Val Ser Asn Tyr 1 5 <210> 192 <400> 192 000 <210> 193 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGU3 CDRL2 long aa <400> 193 Leu Ile Tyr Asp Ala Ser Thr Leu Gln 1 5 <210> 194 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGU3 CDRL3 aa <400> 194 Gln Gln Tyr Asp Ser Leu Pro Leu Thr 1 5 <210> 195 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> MGU3 VH aa <400> 195 Glu Val Leu Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Tyr Ile Ser His Ser Ser Ser Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Arg Pro Leu Ser Tyr Ser Gly Arg Tyr Arg Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 196 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> MGU3 VL aa <400> 196 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Val Ser Asn Tyr 20 25 30 Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Asp Ala Ser Thr Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Ser Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 197 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU3 CDRH1 nuc <400> 197 ggattcacct tcagtgacta taac 24 <210> 198 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU3 CDRH2 nuc <400> 198 attagcata gtagtagtac caca 24 <210> 199 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> MGU3 CDRH3 nuc <400> 199 gcgagacttc gtcccttatc gtatagtggc aggtaccgcg actac 45 <210> 200 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> MGU3 CDRL1 nuc <400> 200 caggacgtta gtaattat 18 <210> 201 <400> 201 000 <210> 202 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGU3 CDRL2 long nuc <400> 202 ctgatctacg atgcatccac tttgcaa 27 <210> 203 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGU3 CDRL3 nuc <400> 203 cagcagtatg atagcctccc actcact 27 <210> 204 <211> 367 <212> DNA <213> Artificial Sequence <220> <223> MGU3 VH nuc <400> 204 gaggtgctac tagtggagtc tgggggaggc ttggtacaac ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt gactataaca tgcactgggt ccgccaggct 120 ccagggaagg ggctggagtg gctttcatac attagtcata gtagtagtac cacatactac 180 gcagactctg tgaggggccg attcaccatc tccagagaca atgccaagaa ctcactgtat 240 ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagacttcgt 300 cccttatcgt atagtggcag gtaccgcgac tactggggcc agggaacgct ggtcaccgtc 360 tcctcag 367 <210> 205 <211> 322 <212> DNA <213> Artificial Sequence <220> <223> MGU3 VL nuc <400> 205 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggcgagtca ggacgttagt aattatgtaa attggtatca gcagaaacca 120 gggaaagccc ctaaggtcct gatctacgat gcatccactt tgcaaacagg ggtcccatca 180 aggttcagtg gaagtggatc ggggacagat tttactttca gcatcagcag cctgcagcct 240 gaagatattg caacatatta ctgtcagcag tatgatagcc tcccactcac tttcggcgga 300 gggaccaagg tggagatcaa ac 322 <210> 206 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU5 CDRH1 aa <400> 206 Gly Phe Ser Phe Ser Ser Tyr Gly 1 5 <210> 207 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU5 CDRH2 aa <400> 207 Ile Trp His Asp Gly Thr Asn Lys 1 5 <210> 208 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> MGU5 CDRH3 aa <400> 208 Thr Lys Arg Ala Gly Trp Gly Asp Ala Leu Asp Ile 1 5 10 <210> 209 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> MGU5 CDRL1 aa <400> 209 Gln Asp Ile Ser Asn Tyr 1 5 <210> 210 <400> 210 000 <210> 211 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGU5 CDRL2 long aa <400> 211 Leu Ile Tyr Asp Ala Ser Asn Leu Glu 1 5 <210> 212 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> MGU5 CDRL3 aa <400> 212 Gln Gln Gln Arg Ile 1 5 <210> 213 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> MGU5 VH aa <400> 213 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45 Ala Leu Ile Trp His Asp Gly Thr Asn Lys Phe Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Lys Arg Ala Gly Trp Gly Asp Ala Leu Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> 214 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> MGU5 VL aa <400> 214 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gln Arg Ile Phe Gly Gly 85 90 95 Gly Thr Lys Val Glu Ile Lys 100 <210> 215 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU5 CDRH1 nuc <400> 215 ggattcagct tcagtagtta tggc 24 <210> 216 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU5 CDRH2 nuc <400> 216 atatggcatg atggaactaa taaa 24 <210> 217 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> MGU5 CDRH3 nuc <400> 217 acgaagcggg ctggctgggg tgatgctctt gatatc 36 <210> 218 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> MGU5 CDRL1 nuc <400> 218 caggacatta gcaactat 18 <210> 219 <400> 219 000 <210> 220 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGU5 CDRL2 long nuc <400> 220 ctgatctacg atgcatccaa tttggaa 27 <210> 221 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> MGU5 CDRL3 nuc <400> 221 caacaacaaa ggatt 15 <210> 222 <211> 358 <212> DNA <213> Artificial Sequence <220> <223> MGU5 VH nuc <400> 222 caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt cagcttcagt agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggattg ggtggctctt atatggcatg atggaactaa taaattttac 180 acagactccg tgaagggccg attcaccatc tccagagaca attccaagga cacactgttt 240 ctgcaaatga acagtctgag agttgaggac acggctgtgt attactgtac gaagcgggct 300 ggctggggtg atgctcttga tatctggggc caagggacaa tggtcaccgt ctcttcag 358 <210> 223 <211> 310 <212> DNA <213> Artificial Sequence <220> <223> MGU5 VL nuc <400> 223 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggcgagtca ggacattagc aactatttaa attggtatca gcagaaacca 120 gggaaagccc ctaaactcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180 aggttcagtg gaagtggatc tgcgacagat tttactctca ccatcagcag cctgcagtct 240 gaagacattg caacatatta ctgtcaacaa caaaggattt tcggcggagg gaccaaggtg 300 gagatcaaac 310 <210> 224 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU8 CDRH1 aa <400> 224 Gly Phe Thr Phe Ser Asn Tyr Gly 1 5 <210> 225 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU8 CDRH2 aa <400> 225 Ile Trp His Asp Gly Thr Asn Lys 1 5 <210> 226 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> MGU8 CDRH3 aa <400> 226 Thr Lys Arg Gly Gly Trp Gly Asp Gly Ser Asp Ile 1 5 10 <210> 227 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> MGU8 CDRL1 aa <400> 227 Gln Asp Val Asp Asn Tyr 1 5 <210> 228 <400> 228 000 <210> 229 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGU8 CDRL2 long aa <400> 229 Leu Ile Tyr Asp Ala Ser Asn Leu Ala 1 5 <210> 230 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> MGU8 CDRL3 aa <400> 230 Gln Gln Gln Arg Ile 1 5 <210> 231 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> MGU8 VH aa <400> 231 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Gly Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile Trp His Asp Gly Thr Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Ser 65 70 75 80 Leu Gln Met Asp Ser Leu Thr Thr Glu Asp Thr Ala Ile Tyr Phe Cys 85 90 95 Thr Lys Arg Gly Gly Trp Gly Asp Gly Ser Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> 232 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> MGU8 VL aa <400> 232 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Val Asp Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln His Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Ala Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Ser Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gln Arg Ile Phe Gly Gly 85 90 95 Gly Thr Arg Val Glu Ile Lys 100 <210> 233 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU8 CDRH1 nuc <400> 233 ggattacct tcagtaacta tggc 24 <210> 234 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU8 CDRH2 nuc <400> 234 atatggcatg atggaactaa taaa 24 <210> 235 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> MGU8 CDRH3 nuc <400> 235 acgaagcgag gtggctgggg tgatggttct gatatc 36 <210> 236 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> MGU8 CDRL1 nuc <400> 236 caggacgttg acaactat 18 <210> 237 <400> 237 000 <210> 238 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGU8 CDRL2 long nuc <400> 238 ctgatctacg atgcatccaa tttggcg 27 <210> 239 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> MGU8 CDRL3 nuc <400> 239 caacaacaaa ggatt 15 <210> 240 <211> 358 <212> DNA <213> Artificial Sequence <220> <223> MGU8 VH nuc <400> 240 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctaagactc 60 tcctgtgcag ccggtggatt taccttcagt aactatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcactt atatggcatg atggaactaa taaattctat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtct 240 ctgcaaatgg acagcctgac aactgaggac acggctatat atttctgtac gaagcgaggt 300 ggctggggtg atggttctga tatctggggc caagggacaa tggtcaccgt ctcttcag 358 <210> 241 <211> 310 <212> DNA <213> Artificial Sequence <220> <223> MGU8 VL nuc <400> 241 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggcgagtca ggacgttgac aactatttaa attggtatca gcataaacca 120 gggaaagccc ctaagctcct gatctacgat gcatccaatt tggcgacagg ggtcccatca 180 aggttcagtg gaagtggatc ttcgacagat tttactctca ccatcagcag cctgcagtct 240 gatgactttg caacatatta ctgtcaacaa caaaggattt tcggcggagg gaccagggtg 300 gaaatcaaac 310 <210> 242 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU10 CDRH1 aa <400> 242 Gly Phe Ala Phe Ser Asn Tyr Gly 1 5 <210> 243 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU10 CDRH2 aa <400> 243 Ile Trp His Asp Gly Ser Leu Lys 1 5 <210> 244 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MGU10 CDRH3 aa <400> 244 Thr Val Trp Tyr Leu Glu Thr Pro Asp Asp Gly Phe Asp Ile 1 5 10 <210> 245 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> MGU10 CDRL1 aa <400> 245 His Gly His Thr Ser Lys Ala 1 5 <210> 246 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> MGU10 CDRL2 aa <400> 246 Val Asn Ser Asp Gly Ser His 1 5 <210> 247 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGU10 CDRL3 aa <400> 247 Gln Ala Trp Asp Ser Gly Ile Trp Val 1 5 <210> 248 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> MGU10 VH aa <400> 248 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Asn Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp His Asp Gly Ser Leu Lys Tyr Tyr Thr Gln Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Ser Ala Asp Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Val Trp Tyr Leu Glu Thr Pro Asp Asp Gly Phe Asp Ile Trp Gly 100 105 110 Arg Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 249 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> MGU10 VL aa <400> 249 Gln Leu Val Leu Thr Gln Pro Pro Ser Ala Ser Ala Ser Leu Gly Val 1 5 10 15 Ser Val Thr Leu Thr Cys Thr Leu Ser His Gly His Thr Ser Lys Ala 20 25 30 Ile Ala Trp His Gln Gln Gln Pro Gly Lys Gly Pro Arg Tyr Leu Met 35 40 45 Lys Val Asn Ser Asp Gly Ser His Thr Lys Gly Ala Ala Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Thr Ser Gly Ala Glu Arg His Phe Thr Ile Ser 65 70 75 80 Asn Leu Gln Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp 85 90 95 Ser Gly Ile Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 250 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU10 CDRH1 nuc <400> 250 ggattcgctt tcagcaatta tggc 24 <210> 251 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU10 CDRH2 nuc <400> 251 atttggcatg acggcagtct taaa 24 <210> 252 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> MGU10 CDRH3 nuc <400> 252 accgtttggt accttgaaac tcctgatgat ggtttcgata tt 42 <210> 253 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MGU10 CDRL1 nuc <400> 253 catggccaca cctccaaagc c 21 <210> 254 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MGU10 CDRL2 nuc <400> 254 gttaatagtg atggcagcca c 21 <210> 255 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGU10 CDRL3 nuc <400> 255 caggcctggg acagtggcat ttgggtt 27 <210> 256 <211> 364 <212> DNA <213> Artificial Sequence <220> <223> MGU10 VH nuc <400> 256 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcatgtgcag cctccggatt cgctttcagc aattatggca tgaactgggt ccgccaggct 120 ccaggcaagg gactggaatg ggtggcagtt atttggcatg acggcagtct taaatattat 180 acacagtccg tgaagggccg attcaccatc tccagagaca atgccaagaa cacgttgttt 240 ctccaaatgg acagcctgag cgctgacgac acggctatgt attattgtac cgtttggtac 300 cttgaaactc ctgatgatgg tttcgatatt tggggccgag ggacaatggt caccgtctcg 360 tcag 364 <210> 257 <211> 334 <212> DNA <213> Artificial Sequence <220> <223> MGU10 VL nuc <400> 257 cagcttgtcc tgactcaacc gccctctgcc tctgcctccc tggggagtctc ggtcaccctc 60 acctgtactc tgagtcatgg ccacacctcc aaagccatcg cgtggcatca acagcagcca 120 gggaagggcc ctcgttattt gatgaaagtt aatagtgatg gcagccacac taagggggcc 180 gctgtccctg atcgcttctc aggctctact tctggggctg agcgccactt caccatctcc 240 aacctccagt ctgacgatga ggctgattat tattgtcagg cctgggacag tggcatttgg 300 gttttcggcg gagggaccaa gttgaccgtc ctag 334 <210> 258 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU11 CDRH1 aa <400> 258 Gly Phe Ser Phe Ser Ser Tyr Gly 1 5 <210> 259 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU11 CDRH2 aa <400> 259 Ile Trp Tyr Asp Gly Thr Asn Lys 1 5 <210> 260 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MGU11 CDRH3 aa <400> 260 Ala Asn Asp Ile Ala Gly Trp Gly Tyr Asp Gly Ser Asn Ala 1 5 10 <210> 261 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> MGU11 CDRL1 aa <400> 261 Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr 1 5 10 <210> 262 <400> 262 000 <210> 263 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGU11 CDRL2 long aa <400> 263 Leu Ile Tyr Lys Val Ser Asn Arg Asp 1 5 <210> 264 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU11 CDRL3 aa <400> 264 Met Gln Gly Thr Val Gly Phe Thr 1 5 <210> 265 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> MGU11 VH aa <400> 265 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Thr Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Asn Asp Ile Ala Gly Trp Gly Tyr Asp Gly Ser Asn Ala Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 266 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> MGU11 VL aa <400> 266 Leu Ser Leu Pro Val Thr Pro Gly Gln Pro Ala Ser Ile Ser Cys Lys 1 5 10 15 Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn Trp 20 25 30 Phe Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Lys Val 35 40 45 Ser Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser 50 55 60 Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val 65 70 75 80 Gly Val Tyr Tyr Cys Met Gln Gly Thr Val Gly Phe Thr Phe Gly Pro 85 90 95 Gly Thr Thr Val Asp Ile Lys 100 <210> 267 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU11 CDRH1 nuc <400> 267 ggattcagct tcagtagcta tggc 24 <210> 268 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU11 CDRH2 nuc <400> 268 atatggtatg atggaaccaa taaa 24 <210> 269 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> MGU11 CDRH3 nuc <400> 269 gcgaatgata ttgcggggtg gggctatgat ggtagtaatg cc 42 <210> 270 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> MGU11 CDRL1 nuc <400> 270 caaaagcctcg tatatagtga tggaaacacc tac 33 <210> 271 <400> 271 000 <210> 272 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGU11 CDRL2 long nuc <400> 272 ctaatttata aggtttctaa ccgggac 27 <210> 273 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU11 CDRL3 nuc <400> 273 atgcaaggta cagtggggtt cact 24 <210> 274 <211> 364 <212> DNA <213> Artificial Sequence <220> <223> MGU11 VH nuc <400> 274 caggtgcagc tggtggagtc tgggggaggc gtagtccagc ctgggaggtc cctgagactc 60 tcctgcgtag cctctggatt cagcttcagt agctatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaaccaa taaatactat 180 gcagattccg tgaagggccg attcaccatc tccagagaca ataccaagaa cacgttgtac 240 ctgcaaatga acagcctgag agcggacgac acggctatgt attactgtgc gaatgatatt 300 gcggggtggg gctatgatgg tagtaatgcc tggggccagg gaaccctggt caccgtctcc 360 tcag 364 <210> 275 <211> 310 <212> DNA <213> Artificial Sequence <220> <223> MGU11 VL nuc <400> 275 ctctccctgc ccgtcacccc tggacagccg gcctccatct cctgcaagtc tagtcaaagc 60 ctcgtatata gtgatggaaa cacctacttg aattggtttc agcagaggcc aggccaatct 120 ccaaggcgcc taatttataa ggtttctaac cgggactctg gggtcccaga cagattcagc 180 ggcagtgggt caggcactga tttcacactg aaaatcagca gggtggaggc tgaggatgtt 240 ggggtttat actgcatgca aggtacagtg gggttcactt tcggccctgg gaccacagtg 300 gatatcaaac 310 <210> 276 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU12 CDRH1 aa <400> 276 Gly Phe Ser Phe Ser Ser Tyr Gly 1 5 <210> 277 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU12 CDRH2 aa <400> 277 Ile Trp His Asp Gly Ser Tyr Ser 1 5 <210> 278 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> MGU12 CDRH3 aa <400> 278 Val Lys Val Glu Asp Tyr Val Arg Gly Ser Ser His Gly Gly Ala Phe 1 5 10 15 His Ile <210> 279 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> MGU12 CDRL1 aa <400> 279 Gln Thr Ile Asn Asn Trp 1 5 <210> 280 <400> 280 000 <210> 281 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGU12 CDRL2 long aa <400> 281 Leu Ile Tyr Lys Ala Ser Ser Leu Glu 1 5 <210> 282 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGU12 CDRL3 aa <400> 282 Gln Gln Tyr Ser Ser Tyr Trp Thr 1 5 <210> 283 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> MGU12 VH aa <400> 283 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35 40 45 Ala Val Ile Trp His Asp Gly Ser Tyr Ser Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Gly Met Tyr His Cys 85 90 95 Val Lys Val Glu Asp Tyr Val Arg Gly Ser Ser His Gly Gly Ala Phe 100 105 110 His Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 125 <210> 284 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> MGU12 VL aa <400> 284 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Asn Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Trp Lys Pro Gly Lys Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Trp Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 105 <210> 285 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU12 CDRH1 nuc <400> 285 ggattcagct tcagtagtta tggc 24 <210> 286 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU12 CDRH2 nuc <400> 286 atttggcatg atggaagtta cagt 24 <210> 287 <211> 54 <212> DNA <213> Artificial Sequence <220> <223> MGU12 CDRH3 nuc <400> 287 gtgaaagttg aggattacgt tagggggagt tcacatgggg gtgcttttca tatc 54 <210> 288 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> MGU12 CDRL1 nuc <400> 288 cagactatta ataactgg 18 <210> 289 <211> 10 <212> DNA <213> Artificial Sequence <220> <223> MGU12 CDRL2 nuc <400> 289 taaggcgtct 10 <210> 290 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGU12 CDRL2 long nuc <400> 290 ctgatctata aggcgtctag tttagaa 27 <210> 291 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGU12 CDRL3 nuc <400> 291 caacagtata gtagttattg gacg 24 <210> 292 <211> 376 <212> DNA <213> Artificial Sequence <220> <223> MGU12 VH nuc <400> 292 caggtacaac tggtggaatc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctccggatt cagcttcagt agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggccggagtg ggtggcagtg atttggcatg atggaagtta cagttactat 180 gcagactccg tgaggggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag acctgaggac acggggatgt atcactgtgt gaaagttgag 300 gattacgtta gggggagttc acatgggggt gcttttcata tctggggcca agggacaatg 360 gtcaccgtct cttcag 376 <210> 293 <211> 319 <212> DNA <213> Artificial Sequence <220> <223> MGU12 VL nuc <400> 293 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtagggga cagagtcacc 60 atcacttgcc gggccagtca gactattaat aactggttgg cctggtatca gtggaaaccg 120 gggaaagccc ctgagctcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tggggacagaa ttcactctca ccatcagcag cctgcagcct 240 gatgattttg caacttatta ctgccaacag tatagtagtt attggacgtt cggccaaggg 300 accaaggtgg acatcaaac 319 <210> 294 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> MGV3 CDRH1 aa <400> 294 Gly Phe Thr Val Ser Asp Ser Tyr 1 5 <210> 295 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> MGV3 CDRH2 aa <400> 295 Ile Tyr Ser Gly Ser Ser Thr 1 5 <210> 296 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> MGV3 CDRH3 aa <400> 296 Ala Arg Gly Pro Asn Asp Tyr Arg Asn Arg Lys Tyr Tyr Tyr Tyr Met 1 5 10 15 Asp Val <210> 297 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> MGV3 CDRL1 aa <400> 297 Gln Ser Val Asp Ser Pro Tyr 1 5 <210> 298 <400> 298 000 <210> 299 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGV3 CDRL2 long aa <400> 299 Leu Ile Phe Gly Ala Ser Ile Arg Ala 1 5 <210>300 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> MGV3 CDRL3 aa <400> 300 His Gln Tyr Gly Asn Ala Pro Tyr Ile 1 5 <210> 301 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> MGV3 VH aa <400> 301 Glu Val Gln Val Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Tyr Gly Phe Thr Val Ser Asp Ser 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Ser Ser Thr Tyr Tyr Ile Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Arg Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Thr Leu Arg Val Glu Asp Thr Ala Leu Tyr Tyr Cys Ala 85 90 95 Arg Gly Pro Asn Asp Tyr Arg Asn Arg Lys Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Ala Val Thr Val Ser Ser 115 120 <210> 302 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> MGV3 VL aa <400> 302 Glu Ile Val Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Ala Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Asp Ser Pro 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Thr Pro Arg Leu Leu 35 40 45 Ile Phe Gly Ala Ser Ile Arg Ala Thr Asp Ile Pro Asp Arg Phe Ser 50 55 60 Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Ser Gly Val Tyr Tyr Cys His Gln Tyr Gly Asn Ala Pro 85 90 95 Tyr Ile Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 303 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> MGV3 CDRH1 nuc <400> 303 ggattcaccg tcagtgacag ctac 24 <210> 304 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MGV3 CDRH2 nuc <400> 304 atctatagtg gtagtagtac a 21 <210> 305 <211> 54 <212> DNA <213> Artificial Sequence <220> <223> MGV3 CDRH3 nuc <400> 305 gcgagaggcc ctaatgacta cagaaatcgc aaatattact actacatgga cgtc 54 <210> 306 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> MGV3 CDRL1 nuc <400> 306 cagagtgttg acagtcccta c 21 <210> 307 <400> 307 000 <210> 308 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGV3 CDRL2 long nuc <400> 308 ctcatttttg gtgcctctat tagggcc 27 <210> 309 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> MGV3 CDRL3 nuc <400> 309 caccagtatg gtaacgcacc ctacatt 27 <210> 310 <211> 373 <212> DNA <213> Artificial Sequence <220> <223> MGV3 VH nuc <400> 310 gaggtgcagg tggtggagtc tgggggagac ttggtccagc cggggggggtc cctgagactc 60 tcctgtgcag tctatggatt caccgtcagt gacagctaca tgagctgggt ccgccaggct 120 ccggggaagg ggctggagtg ggtctcagtt atctatagtg gtagtagtac atactacata 180 gactccgtga agggccgatt caccatctcc agagacaggt ccaagaacac cttgtatctt 240 caaatgaaca ccctgagagt tgaggacacg gctctttatt actgcgcgag aggccctaat 300 gactacagaa atcgcaaata ttactactac atggacgtct ggggcaaagg gaccgcggtc 360 accgtctcct cag 373 <210> 311 <211> 325 <212> DNA <213> Artificial Sequence <220> <223> MGV3 VL nuc <400> 311 gaaattgtgt tgacacagtc tccagacacc ctgtccttgt ctgcagggga aagagtcacc 60 ctctcttgca gggccagtca gagtgttgac agtccctact tagcctggta tcagcaaaga 120 cctggccaga ctcccaggct cctcattttt ggtgcctcta ttagggccac tgacatccca 180 gacaggttca gtggcggtgg gtctgggaca gacttcactc tcaccatcag cagactggaa 240 cctgaagatt ctggagtgta ttactgtcac cagtatggta acgcacccta catttttggc 300 caggggacca agctggagat caaac 325 <210> 312 <211> 102 <212> PRT <213> Artificial Sequence <220> <223> CSP C-terminal peptide 282 - 383 <400> 312 Lys Asn Asn Gln Gly Asn Gly Gln Gly His Asn Met Pro Asn Asp Pro 1 5 10 15 Asn Arg Asn Val Asp Glu Asn Ala Asn Ala Asn Ser Ala Val Lys Asn 20 25 30 Asn Asn Asn Glu Glu Pro Ser Asp Lys His Ile Lys Glu Tyr Leu Asn 35 40 45 Lys Ile Gln Asn Ser Leu Ser Thr Glu Trp Ser Pro Cys Ser Val Thr 50 55 60 Cys Gly Asn Gly Ile Gln Val Arg Ile Lys Pro Gly Ser Ala Asn Lys 65 70 75 80 Pro Lys Asp Glu Leu Asp Tyr Ala Asn Asp Ile Glu Lys Lys Ile Cys 85 90 95 Lys Met Glu Lys Cys Ser 100 <210> 313 <211> 330 <212> PRT <213> Artificial Sequence <220> <223> IgG1 CH1-CH2-CH3 aa <400> 313 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 314 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> IgG CK aa <400> 314 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 315 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> IgG CL aa <400> 315 Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 1 5 10 15 Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp 20 25 30 Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro 35 40 45 Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn 50 55 60 Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys 65 70 75 80 Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val 85 90 95 Glu Lys Thr Val Ala Pro Thr Glu Cys Ser 100 105 <210> 316 <211> 990 <212> DNA <213> Artificial Sequence <220> <223> IgG1 CH1-CH2-CH3 nuc <400> 316 gcgtcgacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaacctgt gacggtctcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg caccagacc 240 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 900 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960 cagaagagcc tctccctgtc cccgggtaaa 990 <210> 317 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> IgG CK nuc <400> 317 cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180 agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240 aaacacaaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300 agcttcaaca ggggagagtg t 321 <210> 318 <211> 318 <212> DNA <213> Artificial Sequence <220> <223> IgG CL nuc <400> 318 ggtcagccca aggctgcccc ctcggtcact ctgttcccgc cctcctctga ggagcttcaa 60 gccaaacaagg ccacactggt gtgtctcata agtgacttct acccgggagc cgtgacagtg 120 gcttggaaag cagatagcag ccccgtcaag gcgggagtgg agaccaccac accctccaaa 180 caaagcaaca acaagtacgc ggccagcagc tatctgagcc tgacgcctga gcagtggaag 240 tcccacagaa gctacagctg ccaggtcacg catgaaggga gcaccgtgga gaagacagtg 300 gcccctacag aatgttca 318 <210> 319 <211> 226 <212> PRT <213> Artificial Sequence <220> <223> HBsAg S domain <400> 319 Met Glu Asn Ile Thr Ser Gly Phe Leu Gly Pro Leu Leu Val Leu Gln 1 5 10 15 Ala Gly Phe Phe Leu Leu Thr Arg Ile Leu Thr Ile Pro Gln Ser Leu 20 25 30 Asp Ser Trp Trp Thr Ser Leu Asn Phe Leu Gly Gly Thr Thr Val Cys 35 40 45 Leu Gly Gln Asn Ser Gln Ser Pro Thr Ser Asn His Ser Pro Thr Ser 50 55 60 Cys Pro Pro Thr Cys Pro Gly Tyr Arg Trp Met Cys Leu Arg Arg Phe 65 70 75 80 Ile Ile Phe Leu Phe Ile Leu Leu Leu Cys Leu Ile Phe Leu Leu Val 85 90 95 Leu Leu Asp Tyr Gln Gly Met Leu Pro Val Cys Pro Leu Ile Pro Gly 100 105 110 Ser Ser Thr Thr Ser Thr Gly Pro Cys Arg Thr Cys Met Thr Thr Ala 115 120 125 Gln Gly Thr Ser Met Tyr Pro Ser Cys Cys Cys Thr Lys Pro Ser Asp 130 135 140 Gly Asn Cys Thr Cys Ile Pro Ile Pro Ser Ser Trp Ala Phe Gly Lys 145 150 155 160 Phe Leu Trp Glu Trp Ala Ser Ala Arg Phe Ser Trp Leu Ser Leu Leu 165 170 175 Val Pro Phe Val Gln Trp Phe Val Gly Leu Ser Pro Thr Val Trp Leu 180 185 190 Ser Val Ile Trp Met Met Trp Tyr Trp Gly Pro Ser Leu Tyr Ser Ile 195 200 205 Leu Ser Pro Phe Leu Pro Leu Leu Pro Ile Phe Phe Cys Leu Trp Val 210 215 220 Tyr Ile 225 <210> 320 <211> 104 <212> PRT <213> Artificial Sequence <220> <223> N-terminus of CSP <400> 320 Met Met Arg Lys Leu Ala Ile Leu Ser Val Ser Ser Phe Leu Phe Val 1 5 10 15 Glu Ala Leu Phe Gln Glu Tyr Gln Cys Tyr Gly Ser Ser Ser Asn Thr 20 25 30 Arg Val Leu Asn Glu Leu Asn Tyr Asp Asn Ala Gly Thr Asn Leu Tyr 35 40 45 Asn Glu Leu Glu Met Asn Tyr Tyr Gly Lys Gln Glu Asn Trp Tyr Ser 50 55 60 Leu Lys Lys Asn Ser Arg Ser Leu Gly Glu Asn Asp Asp Gly Asn Asn 65 70 75 80 Glu Asp Asn Glu Lys Leu Arg Lys Pro Lys His Lys Lys Leu Lys Gln 85 90 95 Pro Ala Asp Gly Asn Pro Asp Pro 100 <210> 321 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 321 Lys Lys Leu Lys Gln Pro Ala 1 5 <210> 322 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 322 His Lys Lys Leu Lys Gln Pro Ala Asp 1 5 <210> 323 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 323 Lys His Lys Lys Leu Lys Gln Pro Ala Asp Gly 1 5 10 <210> 324 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 324 Lys His Lys Lys Leu Lys Gln Pro 1 5 <210> 325 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 325 Arg Lys Pro Lys His Lys Lys Leu Lys Gln Pro 1 5 10 <210> 326 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 326 Pro Lys His Lys Lys Leu Lys Gln Pro Ala Asp Gly Asn 1 5 10 <210> 327 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 327 Lys Pro Lys His Lys Lys Leu Lys Gln Pro Ala Asp Gly Asn Pro 1 5 10 15 <210> 328 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 328 Arg Lys Pro Lys His Lys Lys Leu Lys Gln Pro Ala Asp Gly Asn Pro 1 5 10 15 Asp <210> 329 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 329 Asn Glu Lys Leu Arg Lys Pro Lys His Lys Lys Leu Lys Gln Pro 1 5 10 15 <210> 330 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> N-terminal region of CSP <400> 330 Asn Glu Lys Leu Arg Lys Pro Lys His Lys Lys Leu Lys Gln Pro Ala 1 5 10 15 AspGly <210> 331 <211> 167 <212> PRT <213> Artificial Sequence <220> <223> ferritin polypeptide <400> 331 Met Leu Ser Lys Asp Ile Ile Lys Leu Leu Asn Glu Gln Val Asn Lys 1 5 10 15 Glu Met Asn Ser Ser Asn Leu Tyr Met Ser Met Ser Ser Trp Cys Tyr 20 25 30 Thr His Ser Leu Asp Gly Ala Gly Leu Phe Leu Phe Asp His Ala Ala 35 40 45 Glu Glu Tyr Glu His Ala Lys Lys Leu Ile Val Phe Leu Asn Glu Asn 50 55 60 Asn Val Pro Val Gln Leu Thr Ser Ile Ser Ala Pro Glu His Lys Phe 65 70 75 80 Glu Gly Leu Thr Gln Ile Phe Gln Lys Ala Tyr Glu His Glu Gln His 85 90 95 Ile Ser Glu Ser Ile Asn Asn Ile Val Asp His Ala Ile Lys Gly Lys 100 105 110 Asp His Ala Thr Phe Asn Phe Leu Gln Trp Tyr Val Ala Glu Gln His 115 120 125 Glu Glu Glu Val Leu Phe Lys Asp Ile Leu Asp Lys Ile Glu Leu Ile 130 135 140 Gly Asn Glu Asn His Gly Leu Tyr Leu Ala Asp Gln Tyr Val Lys Gly 145 150 155 160 Ile Ala Lys Ser Arg Lys Ser 165 <210> 332 <211> 265 <212> PRT <213> Artificial Sequence <220> <223> encapsulin polypeptide <400> 332 Met Glu Phe Leu Lys Arg Ser Phe Ala Pro Leu Thr Glu Lys Gln Trp 1 5 10 15 Gln Glu Ile Asp Asn Arg Ala Arg Glu Ile Phe Lys Thr Gln Leu Tyr 20 25 30 Gly Arg Lys Phe Val Asp Val Glu Gly Pro Tyr Gly Trp Glu Tyr Ala 35 40 45 Ala His Pro Leu Gly Glu Val Glu Val Leu Ser Asp Glu Asn Glu Val 50 55 60 Val Lys Trp Gly Leu Arg Lys Ser Leu Pro Leu Ile Glu Leu Arg Ala 65 70 75 80 Thr Phe Thr Leu Asp Leu Trp Glu Leu Asp Asn Leu Glu Arg Gly Lys 85 90 95 Pro Asn Val Asp Leu Ser Ser Leu Glu Glu Thr Val Arg Lys Val Ala 100 105 110 Glu Phe Glu Asp Glu Val Ile Phe Arg Gly Cys Glu Lys Ser Gly Val 115 120 125 Lys Gly Leu Leu Ser Phe Glu Glu Arg Lys Ile Glu Cys Gly Ser Thr 130 135 140 Pro Lys Asp Leu Leu Glu Ala Ile Val Arg Ala Leu Ser Ile Phe Ser 145 150 155 160 Lys Asp Gly Ile Glu Gly Pro Tyr Thr Leu Val Ile Asn Thr Asp Arg 165 170 175 Trp Ile Asn Phe Leu Lys Glu Glu Ala Gly His Tyr Pro Leu Glu Lys 180 185 190 Arg Val Glu Glu Cys Leu Arg Gly Gly Lys Ile Ile Thr Thr Pro Arg 195 200 205 Ile Glu Asp Ala Leu Val Val Ser Glu Arg Gly Gly Asp Phe Lys Leu 210 215 220 Ile Leu Gly Gln Asp Leu Ser Ile Gly Tyr Glu Asp Arg Glu Lys Asp 225 230 235 240 Ala Val Arg Leu Phe Ile Thr Glu Thr Phe Thr Phe Gln Val Val Asn 245 250 255 Pro Glu Ala Leu Ile Leu Leu Lys Phe 260 265

Claims (75)

Antibodies that bind to P. falciparum sporozoites, or antigen-binding fragments thereof,
wherein the antibody, or antigen-binding fragment thereof, binds to the malaria parasite circosporozoite protein according to SEQ ID NO: 24,
wherein the antibody, or antigen-binding fragment thereof, comprises CDRH1, CDRH2, and CDRH3 amino acid sequences and CDRL1, CDRL2, and CDRL3 amino acid sequences according to the following SEQ ID NOs:
(i) SEQ ID NOs: 64 - 68 and 70; (ii) SEQ ID NOs: 64 - 67 and 69 - 70; (iii) SEQ ID NOs: 82 - 86 and 88; (iv) SEQ ID NOs: 82 - 85 and 87 - 88; (v) SEQ ID NOs: 136 - 140 and 142; (vi) SEQ ID NOs: 136 - 139 and 141 - 142; (vii) SEQ ID NOs: 154 - 158 and 160; (viii) SEQ ID NOs: 154 - 157 and 159 - 160; (ix) SEQ ID NOs: 206 - 210 and 212; (x) SEQ ID NOs: 206 - 209 and 211 - 212; (xi) SEQ ID NOs: 224 - 228 and 230; (xii) SEQ ID NOs: 224 - 227 and 229 - 230; (xiii) SEQ ID NOs: 258 - 262 and 264; (xiv) SEQ ID NOs: 258 - 261 and 263 - 264; (xv) SEQ ID NOs: 276 - 280 and 282; (xvi) SEQ ID NOs: 276 - 279 and 281 - 282; (xvii) SEQ ID NOs: 294 - 298 and 300; (xviii) SEQ ID NOs: 294 - 297 and 299 - 300; (xix) SEQ ID NOs: 28 - 32 and 34; (xx) SEQ ID NOs: 28 - 31 and 33 - 34; (xxi) SEQ ID NOs: 46 - 50 and 52; (xxii) SEQ ID NOs: 46 - 49 and 51 - 52; (xxiii) SEQ ID NOs: 100 - 104 and 106; (xxiv) SEQ ID NOs: 100 - 103 and 105 - 106; (xxv) SEQ ID NOs: 118 - 122 and 124; (xxvi) SEQ ID NOs: 118 - 121 and 123 - 124; (xxvii) SEQ ID NOs: 172 - 176 and 178; (xxviii) SEQ ID NO: 172 - 177; (xxix) SEQ ID NOs: 188 - 192 and 194; (xxx) SEQ ID NOs: 188 - 191 and 193 - 194; or (xxxi) SEQ ID NO: 242 - 247. 2. The antibody, or antigen-binding fragment thereof, of claim 1, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region (VH), wherein the heavy chain variable region (VH) has SEQ ID NO: 35, 53, 71, 89, 107, 125, 143 , 161, 178, 195, 213, 231, 248, 265, 283, and 301. An antibody, or antigen-binding fragment thereof, comprising or consisting of an amino acid sequence according to any one of. The antibody, or antigen-binding fragment thereof, of claim 1, wherein the antibody, or antigen-binding fragment thereof comprises:
(i) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 71 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 72; (ii) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 89 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 90; (iii) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 143 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 144; (iv) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 161 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 162; (v) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 213 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 214; (vi) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 231 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 232; (vii) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 265 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 266; (viii) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 283 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 284; (ix) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 301 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 302; (x) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 35 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 36; (xi) a heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 53 or a light chain variable region (VL) amino acid sequence according to SEQ ID NO: 54; (xii) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 107 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 108; (xiii) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 125 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 126; (xiv) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 178 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 179; (xv) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 195 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 196; or (xvi) the heavy chain variable region (VH) amino acid sequence according to SEQ ID NO: 248 or the light chain variable region (VL) amino acid sequence according to SEQ ID NO: 249. The antibody according to any one of claims 1 to 3, wherein the antibody or antigen-binding fragment thereof is a purified antibody, single chain antibody, Fab, Fab', F(ab')2, Fv or scFv. , or an antigen-binding fragment thereof. The antibody, or antigen-binding fragment thereof, according to any one of claims 1 to 3, wherein the antibody, or antigen-binding fragment thereof, is for use as a medicine. The antibody, or antigen-binding fragment thereof, according to any one of claims 1 to 3, wherein the antibody, or antigen-binding fragment thereof, is for use in the prevention or treatment of malaria. A nucleic acid molecule comprising a polynucleotide encoding the antibody according to claim 1, or an antigen-binding fragment thereof. The method of claim 7, wherein the polynucleotide sequence is SEQ ID NO: 37 - 45, 55 - 63, 73 - 81, 91 - 99, 109 - 117, 127 - 135, 145 - 153, 163 - 171, 180 - 187, A nucleic acid molecule comprising or consisting of a nucleic acid sequence according to any one of 197 - 205, 215 - 223, 233 - 241, 250 - 257, 267 - 275, 285 - 293, 303 - 311. A vector comprising the nucleic acid molecule according to claim 7. A cell expressing the antibody, or antigen-binding fragment thereof, comprising the vector according to claim 9. The antibody according to any one of claims 1 to 3, or an antigen-binding fragment thereof, the nucleic acid molecule according to any one of claims 7 to 8, the vector according to claim 9, or the antigen-binding fragment thereof according to claim 10. A pharmaceutical composition for use in the prevention or treatment of malaria, comprising cells. The nucleic acid molecule according to claim 7 or 8 for use in the prevention or treatment of malaria. The vector according to claim 9, for use in the prevention or treatment of malaria. The cell according to claim 10 for use in the prevention or treatment of malaria. An antibody according to any one of claims 1 to 3, or an antigen-binding fragment thereof, a nucleic acid molecule according to any one of claims 7 to 8, a vector according to claim 9, or a vector according to claim 10. containing cells,
A composition for use in monitoring the quality of an anti-malarial vaccine by ensuring that the antigen of the vaccine contains a specific epitope in the correct conformation. The antibody according to any one of claims 1 to 3, or an antigen-binding fragment thereof, the nucleic acid molecule according to any one of claims 7 to 8, the vector according to claim 9, or the antigen-binding fragment thereof according to claim 10. containing cells,
Composition for use in in vitro diagnosis of malaria. An antibody according to any one of claims 1 to 3, or an antigen-binding fragment thereof, a nucleic acid molecule according to any one of claims 7 to 8, a vector according to claim 9, or a vector according to claim 10. Kit of parts containing cells.

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